Method to treat premature ejaculation in humans

ABSTRACT

The present invention belongs to the fields of pharmacology, medicine and medicinal chemistry, and provides methods and compositions for treating sexual dysfunction; more particularly, the invention relates to treatment of premature ejaculation in humans.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application under 35 U.S.C. §371 ofInternational Application No. PCT/US2006/061873 filed Dec. 11, 2006,which claims the benefit of U.S. Provisional Application 60/749,813filed Dec. 13, 2005, the entire disclosures of which are specificallyincorporated herein by reference without disclaimer.

BACKGROUND OF THE INVENTION

Primitive premature ejaculation is regarded as the most common sexualdisorder of the male. This may cause a loss of the ability to achievesexual accommodation which is necessary for the satisfaction of thehuman instinctive desire. Recently, it has been determined that thenumber of cases manifesting various symptoms caused by such loss ofsexual accommodation is rather large. The sexual problems due topremature ejaculation in men lead to social difficulties, such asasthenia due to the loss of self-confidence, as well as domesticdiscord. Premature ejaculation includes persistent or recurrentejaculation before, upon, or shortly after penetration.

By nature, a woman is so evolved that she experiences the sex actmarkedly less intensely than a man, at least at the commencement ofsexual activity. She must, therefore, have more time in order to reachthe orgasm which provides natural relaxation of the whole nervous systemstrained to the maximum during the act. To this day the sense of touchplays an important role in human sex life; particularly sensitive totouch are the erogenous zones, first and foremost among them being theareas where skin borders on mucous membrane as, for example, in thevicinity of the oral cavity, the rectum, female genitals and breastnipples. The erogenous zone of a woman can be her entire body surface.In such cases it is possible to evoke lascivious feelings in her bytouching any part of her body. But it is most often the case thaterogenous zones are localized in strictly defined places such as: theclitoris, labia minora and the vagina. There are, additionally, manysuch sensitive points apart from the sex organs. These are: the lips,the ears, eyelids, neck, nipples, etc. In some cases these points are sosensitive that merely touching them can produce an orgasm in a woman.

However in the case of men, the erogenous zones are confined solely tothe genitals and adjacent areas. It is not surprising, therefore, thatan experienced male partner is sometimes obliged to undertake veritablejourneys of exploration, in his search for these points, without whichno one can activate the complex apparatus of female sexual reflexes.That is one reason the male often needs incomparably less time in orderto reach orgasm—which usually concludes the sex act not only for himselfbut also for his partner. At the commencement of the sex act the manalready finds himself at a certain level of excitement, which isessential to erection and without which this act becomes quiteimpossible. He is unable to continue the act out of consideration forhis partner because immediately after orgasm and the associatedejaculation detumescence takes place and all further frictiones invagina are impossible.

The ideal intercourse would be one in which, following immersing thepenis into the vagina, both parties reached the boundary of orgasmsimultaneously and, having crossed it, ended the sex act together (FIG.1). This happens sometimes where a woman experienced in sexualintercourse can compensate for the excitement missing at the beginningof the act and reach the finishing line together with her partner inspite of that. For young and middle-aged men the norm of normalejaculation vacillates between 2-6 minutes after the immersing the penisinto the vagina.

The premature ejaculation occurs very frequently in the modern humansexual act. It concerns the fact that shortly after immersing the penisinto the vagina takes place (FIG. 2), sometimes after 2-3 movements,ejaculation and orgasm occur; the erection vanishes and the sex act isended. Obviously in such a situation the woman is only aroused, whilethere can be no question of release. Obviously there can be no questionof sexual satisfaction and normal relaxation of the female partner inthe presence of any kind of male impotence, whether through inadequateerection or through premature ejaculation.

Erection of the penis may be a self-perpetuating process of threesteps: 1) vasodilation; 2) release of endogenous smooth-musclerelaxants; and, 3) progression of these effects distal from the initialsite of onset. This has been termed the “cascade effect” (Andersson etal 1995). Papaverine is an opium alkaloid and works as a smooth musclerelaxer possibly by cyclic GMP phosphodiesterase inhibition. It relaxesthe musculature of the vascular system of the penis and increases bloodflow (Papaverine Topical Gel Treatment For Erectile Dysfunction,Urology, Vol. 133(2) (1995), pp. 361-365). Another compound found usefulin the treatment of impotence is prostaglandin E1, a naturally occurringcompound that acts to increase arterial inflow to the penis and may alsorestrict venous outflow. Prostaglandin E1 is preferred to othercompounds used in injections for the treatment of impotence because itis metabolized locally in the penis and is less likely to cause systemicsymptoms such as hypotension. As a modified vascular tissue, corporacavernosa of the penis (ccp) produces and secretes the same range ofautocrine and paracrine regulators as conventional vascular tissue. Thesmooth muscle tone of the ccp, however, does not appear to be regulatedin the same manner as in the vascular wall. Presently it is postulatedthat the tone or contractility of ccp is modulated by adrenergicregulation and locally produced NO and endothelin. In the ccp, moststudies have been directed to observing the relaxing effects of NO(Rajfer et al 1992; Burnett 1995), vasoactive intestinal peptide (VIP),calcitonin gene-related peptide (CGRP) and parasympathetic innervation,which also have similar effects on conventional and ccp vascular smoothmuscle.

During normal penile erections, when the inflow of blood to the ccpengages the sinusoidal spaces, the trabecular tissue compresses smallcavernosal veins against the thick fibrous tissue surrounding thecorpora to maintain the erection. To mediate these changes in bloodflow, nitric oxide is released from postsynaptic parasympathetic neuronsand, to a lesser extent, endothelial cells and α-adrenergic neurons areinhibited in the arterial and trabecular smooth muscle. Nitric oxide,which is readily diffusible, stimulates the formation of increasedcyclic guanosine monophosphate (GMP) in the corpus cavernosum byguanylate cyclase to relax the smooth muscle cells.

Recently, the oral use of the citrate salt of sildenafil has beenapproved by the U.S. Food and Drug Administration (FDA) for thetreatment of male erectile dysfunction. The composition of matter ofsildenafil is first disclosed in the European patent EP 0463756 andthere is no composition of matter patent covering sildenafil in the USor other countries besides the European ones. Sildenafil is reported tobe a selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5(PDE5), the predominant isozyme metabolizing cyclic GMP formed in thecorpus cavernosum (Boolell et al 1996). Since sildenafil is a potentinhibitor of PDE5 in the corpus cavernosum, it is believed to enhancethe effect of nitric oxide, thereby increasing cavernosal blood flow inthe penis, especially with sexual stimulation. Inasmuch as sildenafil atthe currently recommended doses of 25-100 mg has little effect in theabsence of sexual stimulation, sildenafil is believed to restore thenatural erectile response to sexual stimulation but not cause erectionsin the absence of such stimulation (Goldstein 1998). The localizedmechanism by which cyclic GMP stimulates relaxation of the smoothmuscles has not been elucidated.

Normal ejaculatory function in the human male implies a coordinatedsequence of smooth and striate muscular contractions to promoteprojectile, antegrade transport of seminal fluid. This process beginswith transmission of afferent nerve stimuli via the internal pudendalnerve from the penile shaft to higher centers. To complete theejaculatory reflex efferent stimuli are transmitted from theanterolateral columns of the spinal cord and emerging from thethoracolumbar level to comprise a hypogastric or sympathetic plexus.From the interior mesenteric ganglion short adrenergic postganglionicfibers terminate in the seminal vesicles, vasal ampullae, and bladderneck. Sympathetic innervation of the seminal vesicles results in seminalemission into the posterior urethra. Appropriately timed bladder neckclosure prevents retrograde passage of this semen bolus, which ispropelled in the antegrade direction by clonic contracts of thebulbocavernosus and ischiocavernosus muscles of the pelvic floor.Ejaculation is a centrally, integrated peripheral evoked reflex, whichoccurs as a result of α1-adrenergic receptor activation. Effectivepharmacological drugs for the treatment of premature ejaculation exist,but they suffer from severe side effects, for example clomipramine andphenoxybenzamine. Other treatments have a limited effectiveness(metoclopramide and the like).

Dextromethorphan (frequently abbreviated as DM) is the common name for(+)-3-methoxy-N-methylmorphinan (FIG. 3). It widely used as a coughsyrup, and is described in references such as Rodd 1960 (full citationsto articles are provided below) and Goodman and Gilman's PharmacologicalBasis of Therapeutics. Briefly, DM is a non-addictive opioid comprisinga dextrorotatory enantiomer (mirror image) of the morphinan ringstructure which forms the molecular core of most opiates. DM acts at aclass of neuronal receptors known as sigma receptors. These are oftenreferred to as sigma opiate receptors, but there is some question as towhether they are opiate receptors, so many researchers refer to themsimply as sigma receptors, or as high-affinity dextromethorphanreceptors. They are inhibitory receptors, which means that theiractivation by DM or other sigma agonists causes the suppression ofcertain types of nerve signals. Dextromethorphan also acts at anotherclass of receptors known as N-methyl-D-aspartate (NMDA) receptors, whichare one type of excitatory amino acid (EAA) receptor. Unlike its agonistactivity at sigma receptors, DM acts as an antagonist at NMDA receptors,which means that DM suppresses the transmission of nerve impulsesmediated via NMDA receptors. Since NMDA receptors are excitatoryreceptors, the activity of DM as an NMDA antagonist also leads to thesuppression of certain types of nerve signals, which may also beinvolved in some types of coughing. Due to its activity as an NMDAantagonist, DM and one of its metabolites, dextrorphan, are beingactively evaluated as possible treatments for certain types ofexcitotoxic brain damage caused by ischemia (low blood flow) and hypoxia(inadequate oxygen supply), which are caused by events such as stroke,cardiac arrest, and asphyxia. The anti-excitotoxic activity ofdextromethorphan and dextrorphan, and the blockade of NMDA receptors bythese drugs, are discussed in items such as Choi 1987, Wong et al 1988,Steinberg et al 1988, and U.S. Pat. No. 4,806,543 (Choi 1989).Dextromethorphan has also been reported to suppress activity at neuronalcalcium channels (Carpenter et al 1988). Dextromethorphan and thereceptors it interacts with are further discussed in Tortella et al1989, Leander 1989, Koyuncuoglu & Saydam 1990, Ferkany et al 1988,George et al 1988, Prince & Feeser 1988, Feeser et al 1988, Craviso andMusacchio 1983 and Musacchio et al 1988.

DM disappears fairly rapidly from the bloodstream (see, e.g., Vetticadenet al 1989 and Ramachander et al 1977). DM is converted in the liver totwo metabolites called dextrorphan and 3-methoxymorphinan, by anenzymatic process called O-demethylation; in this process, one of thetwo pendant methyl groups is replaced by hydrogen. If the second methylgroup is removed, the resulting metabolite is called 5-hydroxymorphinan.Dextrorphan and 5-hydroxymorphinan are covalently bonded to othercompounds in the liver (primarily glucuronic acid or sulfur-containingcompounds such as glutathione) to form glucuronide or sulfate conjugateswhich are eliminated fairly quickly from the body via urine bloodstream.This enzyme is usually referred to as debrisoquin hydroxylase, since itwas discovered a number of years ago to carry out a hydroxylationreaction on debrisoquin. It is also referred to in various articles asP450DB or P450-2D6. It apparently is identical to an enzyme calledsparteine monooxygenase, which was shown years ago to metabolizesparteine; it was not until recently that scientists realized that asingle isozyme appears to be primarily responsible for oxidizing bothdebrisoquin and sparteine, as well as dextromethorphan and various othersubstrates. Debrisoquin hydroxylase belongs to a family of enzymes knownas “cytochrome P-450” enzymes, or as “cytochrome oxidase” enzymes.Monooxygenation of chemical materials has been ascribed to cytochromesP450 (P450). These hemoprotein containing monooxygenase enzymesdisplaying a reduced carbon monoxide absorption spectrum maximum near450 nm have been shown to catalyze a variety of oxidation reactionsincluding hydroxylation of endogenous and exogenous compounds (Jachau,1990). An extensive amount of research has been conducted on themechanism's by which P450's can catalyze oxygen transfer reactions(Testa and Jenner, 1981; Guengerich, 1992; Brosen et al, 1990; Murray etal, 1990; and Porter et al, 1991).

The P450 reaction cycle proceeds briefly as follows: initial binding ofa substrate molecule (RH) to the ferric form of the cytochrome resultsin the formation of a binary complex and a shift in the spin equilibriumof the ferric enzyme from the low- to high-spin state. Some evidence hasbeen presented that suggests this configuration more readily accepts anelectron from the flavoprotein reductase to form the ferrousP450-substrate complex. However, not all P450s exhibit a relationshipbetween high-spin content and reduction rate. Indeed, it has beenproposed that several factors, including the nature of the P450substrate, the topography of the enzyme/substrate complex, and thepotentials of oxidizable atoms each play a role in regulation of thereduction rate. Molecular oxygen binds to the ferrous P450-substratecomplex to form the ferrous dioxygen complex which is then reduced by asecond electron from the P450 reductase (or perhaps, in some cases, fromreduced nicotinamide adenine dinucleotide via cytochrome b5 and itsreductase). Dioxygen bond cleavage in the reduced ferrous dioxygencomplex results in the insertion of one atom of oxygen into thesubstrate, reduction of the other oxygen atom to water, and restorationof the ferric hemoprotein.

Individual members of the P450 family of enzymes and associated mixedfunction oxidase activities have been described in extrahepatic tissuesincluding brain, adrenal, kidney, testis, ovary, lung and skin.Individual P450s have likewise been characterized in terms of theirinducibility by selected chemical classes. Induction of specific P450enzymes, such as the P450 1A1 and 1A2 subfamily have been extensivelystudied with respect to regulatory processes of increased mRNAtranscription and expression of enzymatic activity. It has beenascertained that materials such as beta-naphthaflavone (beta-NF),3-methylcholanthrene (3-MC), arochlor 1254 (ACLR) and2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are materials that have beencategorized as inducers of P450 enzymes bearing the designated P450 1Asubfamily (Murray et al, 1990; and Guengerich, 1989).

A number of compounds inhibit the activity of the debrisoquinhydroxylase (sparteine monooxygenase) isozyme (Inaba et al 1985). Themost powerful of these inhibitors is quinidine (FIG. 3), adextrorotatory stereoisomer of quinine; it is normally used to treatcardiac arrhythmias. Inaba et al (1986) and Nielsen et al (1990) discussthe ability of quinidine to inhibit the oxidation of sparteine in invivo animal tests, and Brinn et al (1986), Brosen et al (1987), andBroly et al (1989) discuss the ability of quinidine to inhibit DMmetabolism in liver cell preparations. In addition to the inhibition ofdebrisoquin hydroxylase, which is exceptionally potent and easilydemonstrated, other cytochrome P450 isozymes are also likely to besuppressed by quinidine, with varying levels of binding affinity.Accordingly, even though quinidine exerts its most marked effect ondebrisoquin hydroxylase, it is likely to suppress a number of othercytochrome P450 enzymes as well, thereby subjecting a patient to a moregeneral loss of normal and desirable liver activity. The primaryoxidized metabolic product of dextromethorphan is dextrorphan, which iswidely believed among neurologists to be active in exactly the samemanner as dextromethorphan; both drugs reportedly are sigma agonists,NMDA antagonists, and calcium channel antagonists. It has been shownthat the administration of a compound which inhibits debrisoquinhydroxylase, in conjunction with DM, causes a major increase in theconcentration and stability of DM in the blood of patients, compared topatients who receive only DM; and the administration of a debrisoquinhydroxylase inhibitor in conjunction with DM has a clear and substantialimpact on the detectable effects of DM in humans.

Tramadol has the chemical name (+/−)-trans(RR,SS)-2-[(di-methylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, andwhich is often erroneously referred to in literature as the cis(RS,SR)diastereomer. Tramadol is a centrally acting, binary analgesic that isneither opiate-derived, nor is it an NSAID. It is used to controlmoderate pain in chronic pain settings, such as osteoarthritis andpost-operative analgesia, and acute pain, such as dental pain.

Tramadol is a racemate and consists of equal quantities of (+)- and(−)-enantiomers. It is known that the pure enantiomers of tramadol havea differing pharmaceutical profiles and effects when compared to theracemate. The (+)-enantiomer is distinguished by an opiate-likeanalgesic action due its binding with the μ-opiate receptor, and bothenantiomers inhibit 5-hydroxytryptamine (serotonin) and noradrenaline(norepinephrine) reuptake, which is stronger than that of racemicmixtures of tramadol, while distinct inhibition of noradrenalinereuptake is observed with the (−)-enantiomer. It has been proven for(+)- and (−)-tramadol that, depending upon the model, the twoenantiomers mutually reinforce and enhance their individual actions(Raffa, R. et al., 1993; Grond S et al, 1995 and Wiebalck A et al.,1998). It is obvious to conclude that the potent analgesic action oftramadol is based on this mutually dependent reinforcement of action ofthe enantiomers. Tramadol's major active metabolite, O-desmethyltramadol(M1), shows higher affinity for the μ-opiate receptor and has at leasttwice the analgesic potency of the parent drug.O-desmethyl-N-mono-desmethyltramadol (referred to as M5 in some placesin the following text and in the literature) is known as one of the invivo metabolites of tramadol(1RS,2RS)-2[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol(Lintz et al., 1981). M5 penetrates the blood-brain barrier to only alimited extent, as the effects on the central nervous system, forexample analgesic effects, are distinctly less pronounced on intravenousadministration than on intracerebroventricular administration.

Despite the fact that tramadol is chemically unrelated to the opiatesadverse side effects associated with administration of tramadol aresimilar to those of the opiates if used at higher doses.

Caffeine is an alkaloid obtained from the leaves and seeds of the Coffeaarabica or coffee plant and from the leaves of Thea sinensis or tea.Caffeine is a methylated xanthine and chemically denoted as3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (FIG. 3). Althoughcaffeine occurs naturally, it is prepared synthetically for commercialdrug use. Caffeine is the most widely active substance in the world.Average caffeine consumption by adult humans varies among differentcultures and nations from 80 to 400 mg per person per day (Daly 1998).Caffeine elicits a diverse number of pharmacological responses,including increased vigilance, decreased psychomotor reaction time, andincreased sleep latency and waking time and may also influenceintellectual performance (Nehlig 1992). Moreover, caffeine causesrelaxation of smooth muscles, enhances the secretion of gastric acid andthe release of catecholamines, and increases metabolic activity(Fredholm 1999).

Caffeine is essentially non-toxic. The FDA has indicated that no fatalcaffeine poisoning has ever been reported as the result of an overdoseof this compound. The short term lethal dose of caffeine in adults is5-10 grams. At moderate doses, caffeine poses little or no risk ofdevelopmental toxicity for the human fetus. These is no evidence thatconsumption of caffeine is causally related to the development of canceror increased incidence of coronary heart disease. Caffeine is readilyabsorbed after oral, rectal or parenteral administration. Maximal plasmaconcentrations are achieved within 1 hour. Caffeine has a half-life inplasma of 3-7 hours.

Caffeine is the only over-the-counter stimulant that meets the FDAstandards for stimulants. The FDA has concurred that caffeine is bothsafe and effective. The recommended dose is 100-200 mg not to beadministered more often than every 3 or 4 hours. The FDA has noted that,in contrast to the irritating qualities of many coffee extracts,caffeine itself, does not cause irritation of the gastrointestinal tractin the usual doses. This is an advantage when the drug is used for itsstimulant properties. The FDA, in its publications has stated that theevidence establishes that caffeine restores alertness when a person isdrowsy or fatigued.

Although the inhibition of phosphodiesterases may contribute to theactions of caffeine (Daly 1998), there is growing evidence that mostpharmacological effects of this xanthine result from antagonism ofadenosine receptors designated as A₁, A_(2A), A_(2B), and A₃ subtypes(Fredholm 1999). Caffeine acts most potently at A_(2A) receptors,followed closely by A₁ receptors, then A_(2B) receptors (Klotz 1998;Ongini 1996), and as a weak antagonist at human A₃ receptors. Blockadeby caffeine of adenosine receptors, namely the A₁ and the A_(2A)receptor types, inhibits the action of endogenous adenosine on a varietyof physiological processes (Fredholm 1995). Under normal conditions,blood levels of adenosine appear to be sufficient to tonically activateA_(2A) receptors in platelets. Recently, in A_(2A) receptor-knockoutmice, it was reported that platelet aggregation was increased,indicating the importance of this receptor subtype in platelet function(Ledent 1997). It is therefore conceivable that caffeine could blockthese tonically activated A_(2A) receptors in platelets and alter theirfunctions modulated by adenosine.

For many years, an association has been suspected between coffeedrinking and cardiovascular diseases, in particular coronary heartdisease, but recently it has been demonstrated that coffee or caffeineconsumption does not increase the risk of coronary heart diseases orstroke (Grobbee 1990; Jee 1999).

Caffeine is present in several analgesic preparations. To the extentthat this is at all rational it may be related to the presence ofadenosine A_(2A) receptors in or close to sensory nerve endings thatcause hyperalgesia (Ledent et al., 1997). Indeed, caffeine does havehypoalgesic effects in certain types of C-fiber-mediated pain (Myers etal., 1997). The analgesic effects are small (Bättig and Welzl, 1993).Under conditions of pain, however, caffeine could have an indirectbeneficial effect by elevating mood and clear-headedness (Lieberman etal., 1987). In this study it was found that both mood and vigilance weremore improved by aspirin in combination with caffeine than by aspiringiven alone or by placebo. Compositions containing one or more of theanalgesics aspirin, acetaminophen and phenacetin in combination withvarying amounts of caffeine have been marketed in the past. In severalcases, such non-narcotic analgesic/caffeine combination products havefurther included one of the narcotic analgesics codeine, propoxyphene oroxycodone. Examples of these combinations include the products knowncommercially as Excedrin™, SK-65™, Darvon™, Anacin™ and with Codeine,Tabloid™ Brand.

It cannot be excluded that caffeine might have analgesic properties forspecific types of pain, which may be the case for headache (Ward et al.,1991), which is significantly and dose-dependently reduced by caffeineunder double-blind conditions. The effect was similar to that ofacetaminophen, which is frequently combined with caffeine, and showed norelation to the effects on mood or to self-reported coffee drinking. Asreviewed (Migliardi et al., 1994), patients rate caffeine-containinganalgesics as superior to caffeine-free preparations for the treatmentof headache. In addition, caffeine may exert an antinociceptive effectin the brain, because it can antagonize pain-related behavior in themouse following i.c.v. injection (Ghelardini et al., 1997). Moreover,this effect may be related to antagonism of a tonic inhibitory activityof adenosine A₁ receptors that reduce cholinergic transmission (cf.Rainnie et al., 1994; Carter et al., 1995).

As noted above, sleep seems to be one of the physiological functionsmost sensitive to the effects of caffeine in humans. It is well knownthat caffeine taken at bedtime affects sleep negatively (see Snel,1993). Generally, more than 200 mg of caffeine is needed to affect sleepsignificantly. The most prominent effects are shortened total sleeptime, prolonged sleep latency, increases of the initial light sleep EEGstages, and decreases of the later deep sleep EEG stages, as well asincreases of the number of shifts between sleep stages.

At present, the treatment of choice for premature ejaculation ispsychotherapy, either as a behavioural dual team sex therapy accordingto Master & Johnson protocol, or individual psychotherapy (Rifelli andMoro. Sessuologia Clinica. Bologna, 1989). Previous methods of treatingpremature ejaculation include psychological therapies, topicalanesthetics and the use of devices (U.S. Pat. Nos. 5,535,758, 5,063,915,5,327,910, and 5,468,212). All of these methods may have significantdrawbacks. Psychological therapies benefit only a subset of patients andrequire specialized therapists who may not be available to all patients,particularly in remote areas. Furthermore, psychological therapiescannot alleviate premature ejaculation resulting from non-psychologicalcauses. Anesthetic agents decrease sensitivity of tissues, therebydiminishing sexual pleasure. Also, topical anesthetics can betransferred to sexual partners and thereby decrease their sensitivityand pleasure as well. With regard to devices, these can be awkward,inconvenient and embarrassing to use. Devices are highly conspicuous,and reveal the very condition which the suffering partner may prefer toconceal. Additionally, devices can cause irritation to one or bothpartners.

Methods for treating premature ejaculation by systemic administration ofseveral different antidepressant compounds have been described (U.S.Pat. Nos. 4,507,323, 4,940,731, 5,151,448, and 5,276,042; PCTPublication No. WO95/13072). However, these drugs may not be effectivefor all patients, and the side effects of these drugs can halt treatmentor impair patient compliance. Disease states or adverse interactionswith other drugs may contraindicate the use of these compounds orrequire lower dosages that may not be effective to delay the onset ofejaculation. Additionally, the stigma of mental illness associated withantidepressant therapy can discourage patients from beginning orcontinuing such treatments. Administration of the antidepressantfluoxetine has been claimed to treat premature ejaculation (U.S. Pat.No. 5,151,448). However, the administration of fluoxetine may have manyundesired aspects. Patients with hepatic or renal impairments may not beable to use fluoxetine due to its metabolism in the liver and excretionvia the kidney. Systemic events during fluoxetine treatment involvingthe lungs, kidneys or liver have occurred, and death has occurred fromoverdoses. In addition, side effects of oral fluoxetine administrationinclude hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia,anxiety, nervousness, insomnia, drowsiness, fatigue, headache, tremor,dizziness, convulsions, sweating, pruritis, and skin rashes. Fluoxetineinteracts with a range of drugs, often by impairing their metabolism bythe liver.

U.S. Pat. No. 4,940,731 describes the oral or parenteral administrationof sertraline for treating premature ejaculation. It has been recognizedthat sertraline shares many of the same problems as fluoxetine; (seeMartindale, The Extra Pharmacopoeia, 31st edition, at p. 333 (London:The Royal Pharmaceutical Society, 1996)). Sertraline is metabolized inthe liver, and is excreted in the urine and feces. Thus, patients withcirrhosis must take lower doses, and caution must be exercised whenadministering sertraline to patients with renal impairment. Individualstaking monoamine oxidase inhibitors cannot take sertraline due to therisk of toxicity, leading to memory changes, confusion, irritability,chills, pyrexia and muscle rigidity. Side effects resulting from oralsertraline administration include nausea, diarrhea, dyspepsia, insomnia,somnolence, sweating, dry mouth, tremor and mania. Rare instances ofcoma, convulsions, fecal incontinence and gynecomastia have occurred inpatients undergoing sertraline therapy. U.S. Pat. No. 5,276,042describes the administration of paroxetine for the treatment ofpremature ejaculation. Paroxetine is predominantly excreted in theurine, and decreased doses are recommended in patients with hepatic andrenal impairments. Like sertraline, paroxetine cannot be given topatients undergoing treatment with a monoamine oxidase inhibitor. Sideeffects from oral administration of paroxetine include hyponatremia,asthenia, sweating, nausea, decreased appetite, oropharynx disorder,somnolence, dizziness, insomnia, tremor, anxiety, impaired micturition,weakness and paresthesia. Thus there is a need for a method of treatingpremature ejaculation that requires no specialized psychologicaltherapy, can be used conveniently and without embarrassment, and doesnot involve the problems associated with prior therapeutic methods.

U.S. Pat. No. 6,037,360 discloses that administration of variousserotonin agonists and antagonists is effective in the treatment ofpremature ejaculation. The adverse effects occurring most frequentlyduring treatment with serotonin inhibitors are gastrointestinaldisturbances, such as, for example nausea, diarrhoea/loose stools,constipation. (Drugs 43 (Suppl. 2), 1992). Nausea is the main adverseeffect in terms of incidence. Moreover it has been frequently observedthat after administration of serotonin inhibitors, patients suffer fromdyspepsia.

U.S. Pat. No. 5,707,999 teaches that two specific α1-blockers,alfizosine and terazosine, are effective in the treatment of psychogenicpremature ejaculation and said drugs turned out to be effective inpatients who proved to have no benefit from psychological therapy.However terazosine and its analogs have several side effects includingheadache, nausea, weight gain, dizziness, somnolence, dyspnea andblurred vision.

U.S. Pat. No. 6,037,346 discloses the local administration ofphosphodiesterase inhibitors for the treatment of erectile dysfunctionand a preferred mode of administration is claimed as transurethral.Pharmaceutical formulations and kits are provided as well. USapplication US 2002/0037828 A1 discloses the use of phosphodiesteraseinhibitors for treating premature ejaculation.

U.S. Pat. Nos. 4,656,177 and 4,777,174 disclose combinations ofnon-narcotic analgesics/nonsteroidal anti-inflammatory drugs and/ornarcotic analgesics and caffeine. The compositions elicit a more potentand more rapid analgesic response than if the pain reliever is givenalone.

U.S. Pat. No. 4,777,174 discloses combinations of non-narcoticanalgesics/nonsteroidal anti-inflammatory drugs and/or narcoticanalgesics and caffeine. The compositions elicit a more potent and morerapid analgesic response than if the pain reliever is given alone.

U.S. Pat. No. 5,248,678 teaches a method of increasing the arousal andalertness of comatose patients or nea-comatose patients comprisingadministering to the patients effective amounts of an adenosine receptorantagonist, such as caffeine, and a GABA agonist, such as gabapentin.

Heretofore, there has been no recognition or appreciation that acombination of a μ-opiate analgesic such as tramadol and ananalgesia-enhancing amount of dextromethorphan or for that matter, anyother NMDA receptor antagonist can be used effectively to treatpremature ejaculation in humans. Further, heretofore, there has been norecognition or appreciation that a combination of a μ-opiate analgesicsuch as tramadol, a cyclic-GMP-specific phosphodiesterase type 5 (PDE5)inhibitor and an analgesia-enhancing amount of dextromethorphan or forthat matter, any other NMDA receptor antagonist can be used effectivelyto treat premature ejaculation in humans. Further, heretofore, there hasbeen no recognition or appreciation that a combination of a μ-opiateanalgesic such as tramadol, a cyclic-GMP-specific phosphodiesterase type5 (PDE5) inhibitor, caffeine and an analgesia-enhancing amount ofdextromethorphan or for that matter, any other NMDA receptor antagonistcan be used effectively to treat premature ejaculation in humans.

Accordingly, an object of the invention is to provide methods andcompositions for the treatment of premature ejaculation which providewithout the harmful side effects associated with the currently availabletherapy. Surprisingly, it has now been found that a combination of anon-toxic NMDA receptor antagonist such as dextromethorphan with aμ-opiate analgesic such as tramadol exhibit significant palliativeeffects on premature ejaculation. Surprisingly, it has also now beenfound that a combination of a non-toxic NMDA receptor antagonist such asdextromethorphan with a μ-opiate analgesic such as tramadol and acyclic-GMP-specific phosphodiesterase type 5 (PDE5) inhibitor such assildenafil exhibit significant palliative effects on prematureejaculation. These and other objects and features of the invention willbe apparent from the following description.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of effectivelytreating a sexual dysfunction in humans or other mammals. The methodcomprises administering to a patient in need of such treatment an amountof agents including a) an NMDA receptor antagonist or a pharmaceuticallyacceptable salt thereof, and b) a μ-opiate analgesic, which is aμ-opiate receptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof. The combined amount of agentsis effective to treat the sexual dysfunction.

In accordance with the present invention, the sexual dysfunction can bepremature ejaculation or a sexual dysfunction that includes prematureejaculation as a component of the condition.

The agents can be administered separately or in combination. When threeor more agents are involved, the agents can be administered in variouscombinations. For example, three agents can be administered together, ortwo of the agents can be administered together, while the third agent isadministered separately.

The agents are preferably administered prior to sexual activity.Administration can be orally, by means of an implant, parenterally,sub-dermally, sublingually, rectally, topically, or via inhalation. Inpreferred embodiments, the agents are administered orally.

The NMDA receptor antagonist can be dextromethorphan, dextrorphan,ketamine, amantadine, memantine, eliprodil, ifenprodil, phencyclidine,MK-801, dizocilpine, CCPene, flupirtine, or derivatives or saltsthereof. Preferably, the antagonist is dextromethorphan.

The μ-opiate receptor agonist, partial agonist or agonist/antagonist canbe any one of (1R,2R or1S,2S)-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol(tramadol), its N-oxide derivative (“tramadol N-oxide”), and itsO-desmethyl derivative (“O-desmethyl tramadol”) or mixtures,stereoisomers or recemates thereof. In preferred embodiments, theμ-opiate receptor agonist, partial agonist or agonist/antagonist istramadol.

The agents can be administered in a dosage form as a tablet, amultiparticulate formulation for oral administration; a solution, asustained release formulation, a suspension or elixir for oraladministration, an injectable formulation, an implantable device, atopical preparation, a solid state and/or depot type transdermaldelivery device(s), a suppository, a buccal tablet, or an inhalationformulation such as a controlled release particle formulation or spray,mist or other topical vehicle, intended to be inhaled or instilled intothe sinuses. The dosage form can be further defined as a solid oraldosage form formulated as a tablet or capsule.

In accordance with the present invention, the ratio of NMDA receptorantagonist to μ-opiate receptor agonist, partial agonist oragonist/antagonist can be from about 15:1 to 1:15, about 10:1 to 1:10,about 5:1 to 1:5, or about 1:2.

In certain embodiments of the present invention, a phosphodiesterase(PDE) inhibitor or a pharmaceutically acceptable salt thereof isincluded as one of the agents. Preferably, the PDE inhibitor is aphosphodiesterase type 5 inhibitor. The PDE inhibitor can be sildenafil,aminophylline, theophylline, amrinone, milrinone, vesnarinone,vinpocetine, pemobendan, cilostamide, enoximone, peroximone, rolipram,R020-1724, zaniprast, dipyridamole, MY5445, or IC-351, orpharmaceutically acceptable salts thereof. The ratio of NMDA receptorantagonist to phosphodiesterase inhibitor to μ-opiate receptor agonist,partial agonist or agonist/antagonist can be from about 90:1:1 to 1:90:1to 1:1:90.

In certain embodiments, a cytochrome P450 inhibitor or apharmaceutically acceptable salt thereof is included as one of theagents. Preferably, the cytochrome P450 inhibitor is a debrisoquinhydroxylase inhibitor. The inhibitor can be quinidine, quinine,naphthyridine, xanthine, phenoxy amino alkane, carbamoyl imidazole, aguanidine imidazole, cimetidine(N-cyano-N′-methyl-N″-[2[[(5-methyl-1H-imidazol-4yl)methyl]thio]ethyl]guanidine), a quinoline, chloroquine(7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline), primaquine(8-(4-amino-1-methylbutylamino)-6-methoxyquinoline), a trifluoromethyloxime ether, fluvoxamine, also known as5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1 pentanone 0-(2-aminoethyl)oxime, or pharmaceutically acceptable salts thereof. The ratio of NMDAreceptor antagonist to cytochrome P450 inhibitor to μ-opiate receptoragonist, partial agonist or agonist/antagonist can be from about 90:1:1to 1:90:1 to 1:1:90.

In certain embodiments, caffeine is included as one of the agents.

In further embodiments of the present invention, both aphosphodiesterase inhibitor and a cytochrome P450 inhibitor are includedas agents. In further embodiments of the present invention, both aphosphodiesterase inhibitor and caffeine are included as agents. Infurther embodiments of the present invention, both caffeine and acytochrome P450 inhibitor are included as agents. In further embodimentsof the present invention, both a phosphodiesterase inhibitor, caffeineand a cytochrome P450 inhibitor are included as agents.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of acombination of agents. The combination comprises a) an NMDA receptorantagonist or a pharmaceutically acceptable salt thereof, b) a μ-opiatereceptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, and c) a phosphodiesterasetype V inhibitor or a pharmaceutically acceptable salt thereof. Incertain embodiments, the pharmaceutical composition further comprisescaffeine as an agent.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a combination ofagents, the combination comprising a) an NMDA receptor antagonist or apharmaceutically acceptable salt thereof, b) a μ-opiate receptoragonist, partial agonist or agonist/antagonist, or a pharmaceuticallyacceptable salt thereof, and c) a cytochrome P450 inhibitor or apharmaceutically acceptable salt thereof. In certain embodiments, thepharmaceutical composition further comprises caffeine as an agent.

The present invention further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a combination ofagents, the combination comprising a) an NMDA receptor antagonist or apharmaceutically acceptable salt thereof, b) a μ-opiate receptoragonist, partial agonist or agonist/antagonist, or a pharmaceuticallyacceptable salt thereof, c) a phosphodiesterase type V inhibitor or apharmaceutically acceptable salt thereof, and d) a cytochrome P450inhibitor or a pharmaceutically acceptable salt thereof. In certainembodiments, the pharmaceutical composition further comprises caffeineas an agent.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of acombination of agents. The combination comprises a) an NMDA receptorantagonist or a pharmaceutically acceptable salt thereof, b) a μ-opiatereceptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, and c) caffeine.

In accordance with the present invention, Applicants have now developedcompositions, (combinations and formulations) which are administered toa human in the treatment of premature ejaculation. These compositions,(combinations and formulations) employ, combine, or incorporate (as thecase may be) a plurality of effective non-toxic dosage amounts, eachdosage amount comprising an effective non-toxic dosage amount of a drug,for example, a μ-opiate analgesic, for example, tramadol (or saltthereof), an effective non-toxic dosage amount of an NMDA receptorantagonist such as dextromethorphan (preferably dextromethorphan hydrateor salt thereof), a PDE5 inhibitor (e.g., sildenafil) and optionally, aneffective non-toxic dosage amount of a cytochrome-P450 inhibitor, forexample, quinidine (preferably quinidine hydrate or salt thereof).

Applicants have also developed compositions, (combinations andformulations) which are administered to a human in the treatment ofpremature ejaculation and erection. These compositions, (combinationsand formulations) employ, combine, or incorporate (as the case may be) aplurality of effective non-toxic dosage amounts, each dosage amountcomprising an effective non-toxic dosage amount of a drug which inhibitscyclic-GMP-specific phosphodiesterase type 5 (PDE5), for example,sildenafil (or salt thereof), an effective non-toxic dosage amount of anNMDA receptor antagonist such as dextromethorphan (preferablydextromethorphan hydrate or salt thereof), caffeine and an effectivenon-toxic dosage amount of a μ-opiate analgesic, for example, tramadol(or salt thereof).

Accordingly, a further aspect of the subject invention is the disclosurethat a combination of a μ-opiate analgesic such as tramadol, an NMDAreceptor antagonist such as dextromethorphan which involves inanti-excitotoxic activity in humans, and optionally a cytochrome P450inhibitor such as quinidine, is very effective in delaying the onset ofejaculation in male humans.

According to yet another aspect of the invention, applicants haveprovided pharmaceutical compositions (combinations and formulations)comprising a plurality of dosage amounts each comprising, together withpharmaceutical excipients suitable for oral or parenteraladministration, a therapeutically effective amount of agents. The amountis effective to treat and to assist to resolve diseases and conditionsof premature ejaculation in the human male in a manner that is non-toxicto the patient. The therapeutically effective dosage amount of agentsincludes a μ-opiate analgesic, for example tramadol, and an effectivenon-toxic dosage amount of an NMDA receptor antagonist such asdextromethorphan and/or salts thereof (for example the hydrobromidesalt) and/or homologues, analogues, derivatives, complexes, prodrugs,esters, and/or fragments thereof, and optionally an effective non-toxicdosage amount of a cytochrome-P450 inhibitor, for example, quinidine(preferably quinidine hydrate or salt thereof).

It is another aspect of the invention to provide a method wherein eachpharmacologically active agent is administered orally. It is a furtheraspect of the invention to provide a method wherein eachpharmacologically active agent is administered parenterally.

The present invention provides a method for treating prematureejaculation, the method comprising administering to an individual inneed of such treatment a pharmaceutical formulation containing aμ-opiate analgesic such as tramadol, an NMDA receptor antagonist such asdextromethorphan, and optionally an agent which inhibits the oxidativeactivity of cytochrome-P450, such as a naphthyridine, xanthine, phenoxyamino alkane, carbamoyl imidazole, guanidine imidazole, e.g. cimetidine(N-cyano-N′-methyl-N″-[2[[(5-methyl-1H-imidazol-4yl)methyl]thio]ethyl]guanidine), quinoline, e.g. chloroquine(7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline) and primaquine(8-(4-amino-1-methylbutylamino)-6-methoxyquinoline), a trifluoromethyloxime ether, e.g., fluvoxamine, also known as5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1 pentanone 0-(2-aminoethyl)oxime. Administration of the pharmaceutical formulation is carried outwithin the context of a predetermined dosing regimen such that the agentis effective in the treatment of premature ejaculation. Drug deliverymay be accomplished through any route effective to provide relief frompremature ejaculation, including oral, parenteral, buccal, rectal,topical, transdermal, transurethral, and intracavernosal injection.

In accordance with the invention, a pharmaceutical formulation isprovided for carrying out the method of the invention. Thepharmaceutical formulation comprises an effective amount of a selectedμ-opiate analgesic such as tramadol, an NMDA receptor antagonist such asdextromethorphan, optionally, a cytochrome-P450 inhibitor, apharmacologically acceptable carrier or vehicle, and, optionally (i.e.,in topical, transdermal or transurethral formulations), an enhancer.Other types of components may be incorporated into the formulation aswell, e.g., excipients, surfactants, preservatives (e.g., antioxidants),stabilizers, enzyme inhibitors, chelating agents, and the like, as willbe appreciated by those skilled in the art of pharmaceutical formulationpreparation and drug delivery.

Yet another aspect of the subject invention is the disclosure that acombination of cyclic-GMP-specific phosphodiesterase type 5 (PDE5)inhibitors such as sildenafil which facilitates the erection of thepenis in humans under sexual stimulation, an NMDA receptor antagonistsuch as dextromethorphan which involves in anti-excitotoxic activity inhumans, a μ-opiate analgesic such as tramadol, and optionally acytochrome P450 inhibitor such as quinidine, is very effective indelaying the onset of ejaculation in male humans who have erection aswell as ejaculation problems.

Thus, according to yet another aspect of the invention, applicants haveprovided pharmaceutical compositions (combinations and formulations)comprising a plurality of dosage amounts each comprising, together withpharmaceutical excipients suitable for oral or parenteraladministration, a therapeutically effective (to treat and to assist toresolve diseases and conditions of premature ejaculation in human malenon-toxic to the patient) dosage amount of a drug for example whichinhibits cyclic-GMP-specific phosphodiesterase type 5 (PDE5), forexample, sildenafil, and an effective non-toxic dosage amount dosageamount of an NMDA receptor antagonist such as dextromethorphan and/orsalts thereof (for example the hydrobromide salt) and/or homologues,analogues, derivatives, complexes, prodrugs, esters, and/or fragmentsthereof, and an effective non-toxic dosage amount of a μ-opiateanalgesic such as tramadol and/or salts thereof (for example thehydrobromide salt) and/or homologues, analogues, derivatives, complexes,prodrugs, esters, and/or fragments thereof. Drug delivery may beaccomplished through any route effective to provide relief frompremature ejaculation, including oral, parenteral, buccal, rectal,topical, transdermal, transurethral, and intracavernosal injection.

As with compositions containing a cytochrome P450 inhibitor,compositions containing a PDE5 inhibitor can also comprise apharmacologically acceptable carrier or vehicle, and, optionally (i.e.,in topical, transdermal or transurethral formulations), an enhancer.Other types of components may be incorporated into the formulation aswell, e.g., excipients, surfactants, preservatives (e.g., antioxidants),stabilizers, enzyme inhibitors, chelating agents, and the like, as willbe appreciated by those skilled in the art of pharmaceutical formulationpreparation and drug delivery.

In practicing the present invention, the NMDA antagonist and/or at leastone pharmaceutically acceptable salt thereof can be administered before,simultaneously with, or after administration of the tramadol or otherμ-opiate agonist or agonist/antagonist and/or at least onepharmaceutically acceptable salt thereof, such that the dosing intervalof the a NMDA antagonist and/or at least one pharmaceutically acceptablesalt thereof overlaps with the dosing interval of the tramadol or otherμ-opiate agonist or agonist/antagonist and/or at least onepharmaceutically acceptable salt thereof.

Also, the cyclic-GMP-specific phosphodiesterase type 5 (PDE5) inhibitor,the cytochrome P450 inhibitor, and/or at least one pharmaceuticallyacceptable salt thereof can be administered before, simultaneously with,or after administration of the tramadol or other μ-opiate agonist oragonist/antagonist and/or at least one pharmaceutically acceptable saltthereof and the NMDA antagonist and/or at least one pharmaceuticallyacceptable salt thereof, such that the dosing interval of thecyclic-GMP-specific phosphodiesterase type 5 (PDE5) inhibitor, thecytochrome P450 inhibitor, and/or at least one pharmaceuticallyacceptable salt thereof overlaps with the dosing interval of thetramadol or other μ-opiate agonist or agonist/antagonist and/or at leastone pharmaceutically acceptable salt thereof and the dosing interval ofthe NMDA antagonist and/or at least one pharmaceutically acceptable saltthereof. Caffeine may also be administered prior to, during, or afterthe administration of a PDE5 inhibitor, a μ-opiate antagonist or acytochrome P450 inhibitor to treat premature ejaculation. An additionaladvantage in using caffeine in the compositions and methods of thepresent invention is that it may be used to offset drowsiness orsedation which may be experienced by users of opiate analgesic.

The present invention may be further understood by reference to theembodiments in the following numbered sentences:

1. A method of effectively treating a sexual dysfunction in humans orother mammals, comprising administering to a patient in need of suchtreatment an amount of agents including a) an NMDA receptor antagonistor a pharmaceutically acceptable salt thereof, and b) a μ-opiatereceptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, whereby the combined amount ofsaid agents is effective to treat the sexual dysfunction.

2. The method of sentence 1, wherein the sexual dysfunction is prematureejaculation.

3. The method of sentence 1, wherein the agents are administeredseparately.

4. The method of sentence 1, wherein the agents are administered incombination.

5. The method of sentence 1, wherein the agents are administered priorto sexual activity.

6. The method of sentence 1, wherein the agents are administered orally,by means of an implant, parenterally, sub-dermally, sublingually,rectally, topically, or via inhalation.

7. The method of sentence 6, wherein the agents are administered orally.

8. The method of sentence 1, wherein the NMDA receptor antagonist isdextromethorphan, dextrorphan, ketamine, amantadine, memantine,eliprodil, ifenprodil, phencyclidine, MK-801, dizocilpine, CCPene,flupirtine, or derivatives or salts thereof.

9. The method of sentence 8, wherein the NMDA receptor antagonist isdextromethorphan.

10. The method of sentence 1, wherein the a μ-opiate receptor agonist,partial agonist or agonist/antagonist is any one of (1R,2R or1S,2S)-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol(tramadol), its N-oxide derivative (“tramadol N-oxide”), and itsO-desmethyl derivative (“O-desmethyl tramadol”) or mixtures,stereoisomers or recemates thereof.

11. The method of sentence 10, wherein the μ-opiate receptor agonist,partial agonist or agonist/antagonist is tramadol.

12. The method of sentence 1 wherein the agents are administered in adosage form selected from the group consisting of a tablet, amultiparticulate formulation for oral administration; a solution, asustained release formulation, a suspension or elixir for oraladministration, an injectable formulation, an implantable device, atopical preparation, a solid state and/or depot type transdermaldelivery device(s), a suppository, a buccal tablet, or an inhalationformulation such as a controlled release particle formulation or spray,mist or other topical vehicle, intended to be inhaled or instilled intothe sinuses.

13. The method of sentence 12, wherein the dosage form is furtherdefined as a solid oral dosage form formulated as a tablet or capsule.

14. The method of sentence 1, wherein the ratio of NMDA receptorantagonist to μ-opiate receptor agonist, partial agonist oragonist/antagonist is from about 15:1 to 1:15.

15. The method of sentence 14, wherein the ratio of NMDA receptorantagonist to μ-opiate receptor agonist, partial agonist oragonist/antagonist is from about 10:1 to 1:10.

16. The method of sentence 15, wherein the ratio of NMDA receptorantagonist to μ-opiate receptor agonist, partial agonist oragonist/antagonist is from about 5:1 to 1:5.

17. The method of sentence 16, wherein the ratio of NMDA receptorantagonist to μ-opiate receptor agonist, partial agonist oragonist/antagonist is about 1:2.

18. The method of sentence 1, wherein a phosphodiesterase inhibitor, ora pharmaceutically acceptable salt thereof, is included as an agent.

19. The method of sentence 18, wherein the phosphodiesterase inhibitoris a phosphodiesterase type V inhibitor.

20. The method of sentence 18, wherein the phosphodiesterase inhibitoris sildenafil, aminophylline, theophylline, amrinone, milrinone,vesnarinone, vinpocetine, pemobendan, cilostamide, enoximone,peroximone, rolipram, R020-1724, zaniprast, dipyridamole, MY5445, orIC-351, or pharmaceutically acceptable salts thereof.

21. The method of sentence 18, wherein the ratio of NMDA receptorantagonist to phosphodiesterase inhibitor to μ-opiate receptor agonist,partial agonist or agonist/antagonist is from about 90:1:1 to 1:90:1 to1:1:90.

22. The method of sentence 1 or 18, wherein a cytochrome P450 inhibitor,or a pharmaceutically acceptable salt thereof, is included as an agent.

23. The method of sentence 22, wherein the cytochrome P450 inhibitor isa debrisoquin hydroxylase inhibitor.

24. The method of sentence 22 wherein the cytochrome P450 inhibitor isquinidine, quinine, naphthyridine, xanthine, phenoxy amino alkane,carbamoyl imidazole, a guanidine imidazole, cimetidine(N-cyano-N′-methyl-N″-[2[[(5-methyl-1H-imidazol-4yl)methyl]thio]ethyl]guanidine), a quinoline, chloroquine(7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline), primaquine(8-(4-amino-1-methylbutylamino)-6-methoxyquinoline), a trifluoromethyloxime ether, fluvoxamine, also known as5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1 pentanone 0-(2-aminoethyl)oxime, or pharmaceutically acceptable salts thereof.

25. The method of sentence 22, wherein the ratio of NMDA receptorantagonist to cytochrome P450 inhibitor to μ-opiate receptor agonist,partial agonist or agonist/antagonist is from about 90:1:1 to 1:90:1 to1:1:90

26. The method of sentence 1, 18 or 22, wherein caffeine is included asan agent.

27. A pharmaceutical composition comprising a therapeutically effectiveamount of a combination of agents, the combination comprising a) an NMDAreceptor antagonist or a pharmaceutically acceptable salt thereof, b) aμ-opiate receptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, and c) a phosphodiesterasetype V inhibitor, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a therapeutically effectiveamount of a combination of agents, the combination comprising a) an NMDAreceptor antagonist or a pharmaceutically acceptable salt thereof, b)μ-opiate receptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, and c) a cytochrome P450inhibitor, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a therapeutically effectiveamount of a combination of agents, the combination comprising a) an NMDAreceptor antagonist or a pharmaceutically acceptable salt thereof, b) aμ-opiate receptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, c) a phosphodiesterase type Vinhibitor, or a pharmaceutically acceptable salt thereof, and d) acytochrome P450 inhibitor, or a pharmaceutically acceptable saltthereof.

30. The pharmaceutical composition of sentence 27, 28, or 29, whereinthe pharmaceutical composition further comprises caffeine.

31. A pharmaceutical composition comprising a therapeutically effectiveamount of a combination of agents, the combination comprising a) an NMDAreceptor antagonist or a pharmaceutically acceptable salt thereof, b) aμ-opiate receptor agonist, partial agonist or agonist/antagonist, or apharmaceutically acceptable salt thereof, and c) caffeine.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description which follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing orgasm levels during normal sexualintercourse. Orgasm levels in a man and woman during normal sexualintercourse are shown. The orgasm level is an arbitrary quantitydescribing the physical and emotional excitements during sexualintercourse.

FIG. 2 is a graph showing orgasm levels in the case of prematureejaculation. The orgasm levels in male and female in the case ofpre-mature ejaculation are shown. The orgasm level is an arbitraryquantity describing the physical and emotional excitements during sexualintercourse.

FIG. 3 provides the chemical structures of tramadol, quinidine,dextromethorphan, caffeine, and sildenafil.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particular drugs ordrug delivery systems, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting. It mustbe noted that, as used in this specification, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a pharmacologicallyactive agent” includes a combination of two or more pharmacologicallyactive agents, and the like. In describing the present invention, thefollowing terminology will be used in accordance with the definitionsset out below.

The terms “active agent,” “drug” and “pharmacologically active agent”are used interchangeably herein to refer to a chemical material orcompound which, when administered to an organism (human or animal)induces a desired pharmacologic effect. Included are derivatives andanalogs of those compounds or classes of compounds specificallymentioned which also induce the desired pharmacologic effect.

The term “topical administration” is used in its conventional sense tomean delivery of a topical drug or pharmacologically active agent to theskin or mucosa.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for drug administration. Carriers and vehicles useful hereininclude any such materials known in the art, e.g., any liquid, gel,solvent, liquid diluent, solubilizer, or the like, which is nontoxic andwhich does not interact with other components of the composition in adeleterious manner.

By an “effective” amount of a drug or pharmacologically active agent ismeant a nontoxic but sufficient amount of the drug or agent to providethe desired effect.

The term “premature ejaculation” as used herein intends a sexualdysfunction wherein a male is unable to control the ejaculatory processto a degree sufficient to satisfy a partner. Generally, “prematureejaculation” refers to persistent or recurring ejaculation with minimalstimulation before or during sexual intercourse. The term includes both“congenital” or “lifelong” premature ejaculation and “primary” or“acquired” premature ejaculation as set forth, for example, in U.S. Pat.No. 5,151,448, and in Male Infertility and Sexual Dysfunction at p. 356(New York: Springer-Verlag, 1997). See also Diagnostic and StatisticalManual of Mental Disorders (Washington, D.C.: American PsychiatricAssociation, 1994).

The term “NSAID” refers to non-steroidal substances which inhibit theproduction of prostaglandins by binding with cyclo-oxygenase enzymes.The compound acetaminophen is included under this category even thoughacetaminophen does not have anti-inflammatory properties but bind withcyclo-oxygenase enzymes in the periphery and at the hypothalamicthermoregulatory center.

The term “sildenafil” as used herein includes the free base form of thiscompound as well as pharmacologically acceptable acid addition saltsthereof formed with organo-carboxylic acids, organo-sulphonic acids orinorganic acids. For purposes of the present invention, theorgano-carboxylic acid salt, sildenafil citrate, having a solubility inwater of 3.5 mg/ml is particularly preferred. Reference to “sildenafil”includes sildenafil citrate.

The term “caffeine” as used herein is intended to encompass not onlycaffeine as the anhydrous powder, but any salt or derivative of caffeineor any compounded mixture thereof which is non-toxic, pharmaceuticallyacceptable and which is capable of hastening and enhancing an analgesicor anti-inflammatory response when employed as described herein (See,for example, The Merck Index, ninth edition, Merck & Co., Inc. Rahway,N.J. (1976), pp. 207-208, for a description of caffeine salts,derivatives and mixtures that may prove useful in the compositions ofthe present invention). Nevertheless, caffeine as the anhydrous powderbase is presently preferred and, where specific amounts of caffeine areset forth below, such amounts are given in mg of the anhydrous base.

The inventors were searching for an effective treatment of prematureejaculation. Based on the previous arts described above the inventorsreasoned that in order to control the ejaculation process for males whodo not have any erection problem and to have satisfactory sexualintercourse (hereinafter referred to as CLASS I), the ejaculationprocess has to be delayed so that the sexual partners would havesufficient time for intercourse to reach maximum sexual satisfaction.

In the case of males who have erection problem and can not controlejaculation once erection is achieved the following two steps have to bepreferred; (1) the erection has to be achieved through certainpharmaceutical agents such as sildenafil such that the male will havefull erection upon the stimulation by the sexual partner; (2) theejaculation process has to be delayed so that the sexual partners wouldhave sufficient time for intercourse to reach maximum sexualsatisfaction (hereinafter referred to as CLASS II).

It is understood that the administration of DM has the anti-excitotoxiceffect in humans and the administration of DM to human male would havean effect on the ejaculation process. It is also understood thattramadol has analgesic effect due to their action on the nerve signals.Further it is understood that administration of a debrisoquinhydroxylase inhibitor or a cytochrome-P450 inhibitor concurrently withDM substantially increases the observable therapeutic effects of DM inhuman clinical trials, then the effectiveness of DM as an agent fortreating premature ejaculation can also be increased by theco-administration of a cytochrome oxidase inhibitor. Based on theseobservations the inventors reasoned that administration of a combinationof these agents would have a therapeutical effect on prematureejaculation for CLASS I males. To their surprise, they now discoveredthat ingestion of these agents indeed has profound effects on thepremature ejaculation and that they prolong the sexual intercourse toreach maximal orgasm. Further they observed that these agents can beused to have multiple orgasm during sexual intercourse.

In addition, the inventors have discovered that ingestion of sildenafil,tramadol and DM has profound effects on the premature ejaculation inCLASS II males and that they prolong the sexual intercourse to reachmaximal orgasm. Further they observed that these agents can be used tohave multiple orgasm during sexual intercourse. Further the inventorshave discovered that ingestion of tramadol along with sildenafil and DMdoes not affect the therapeutical effect of sildenafil and DMcombination in treating premature ejaculation in CLASS II patients.

Additionally, in certain embodiments of the present invention, theaddition of caffeine to the above composition has the advantage tooffset the drowsiness or sedation experienced by some of the users ofopiate analgesic.

Active Agents for Treating Premature Ejaculation in CLASS I Males

In order to carry out the method of the invention to treat prematureejaculation in CLASS I males, selected pharmacologically active agent(s)is administered to an individual. The active agents may be administeredorally, parenterally, buccally, rectally, or locally by intracavernosalinjection or by delivery to the urethra. Suitable pharmacologicallyactive agents include: μ-opiate analgesic tramadol, its metabolites,salts thereof.

(+/−)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine(Shipton E A 2000). It is a central analgesic with a low affinity foropiate receptors. Its selectivity for mu receptors has recently beendemonstrated, and the M1 metabolite of tramadol, produced by liverO-demethylation, shows a higher affinity for opiate receptors than theparent drug. The rate of production of this M1 derivative (O-demethyltramadol), is influenced by a polymorphic isoenzyme of thedebrisoquine-type, cytochrome P450 2D6 (CYP2D6). One mechanism relatesto its weak affinity for μ-opiate receptors (6,000-fold less thanmorphine, 100-fold less than d-propoxyphene, 10-fold less than codeine,and equivalent to dextromethorphan). Moreover, and in contrast to otheropiates, the analgesic action of tramadol is only partially inhibited bythe opiate antagonist naloxone, which suggests the existence of anothermechanism of action. This was demonstrated by the discovery of amonoaminergic activity that inhibits noradrenaline (norepinephrine) andserotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significantcontribution to the analgesic action by blocking nociceptive impulses atthe spinal level (Dayer et al. 1994 & 1997).

(+/−)-Tramadol is a racemic mixture of 2 enantiomers, each onedisplaying differing affinities for various receptors. (+/−)-tramadol isa selective agonist of μ receptors and preferentially inhibits serotoninreuptake, whereas (−)-tramadol mainly inhibits noradrenaline reuptake.The action of these 2 enantiomers is both complementary and synergisticand results in the analgesic effect of (+/−)-tramadol. After oraladministration, tramadol demonstrates 68% bioavailability, with peakserum concentrations reached within 2 hours. The elimination kineticscan be described as 2-compartmental, with a half-life of 5.1 hours fortramadol and 9 hours for the M1 derivative after a single oral dose of100 mg. This explains the approximately 2-fold accumulation of theparent drug and its M1 derivative that is observed during multiple dosetreatment with tramadol. The recommended daily dose of tramadol isbetween 50 and 100 mg every 4 to 6 hours, with a maximum dose of 400mg/day. The duration of the analgesic effect after a single oral dose oftramadol 100 mg is about 6 hours. Adverse effects, and nausea inparticular, are dose dependent and therefore considerably more likely toappear if the loading dose is high. The reduction of this dose duringthe first days of treatment is an important factor in improvingtolerability. Other adverse effects are generally similar to those ofopiates, although they are usually less severe, and can includerespiratory depression, dysphoria and constipation. Tramadol can beadministered concomitantly with other analgesics, particularly thosewith peripheral action, while drugs that depress CNS function mayenhance the sedative effect of tramadol. Tramadol has pharmacodynamicand pharmacokinetic properties that are highly unlikely to lead todependence. This was confirmed by various controlled studies andpostmarketing surveillance studies, which reported an extremely smallnumber of patients developing tolerance or instances of tramadol abuse(Raffa et al. 1993; Lee et al. 1993)

In certain embodiments of the present invention, premature ejaculationmay be treated without the harmful side effects associated withtraditional analgesics, such as respiratory depression, disturbed sleeppatterns, diminished appetite, seizures, and psychological and/orphysical dependency.

Although it has proven to be a safe and effective agent for the controlof pain, adverse effects can occur with its use. It has been reportedthe occurrence of seizure activity after the inadvertent administrationof 4 mg/kg of tramadol to a child (Tobias 1997).

Dextromethorphan acts at a class of neuronal receptors known as sigmareceptors. They are inhibitory receptors, meaning that their activationby DM or other sigma agonists causes the suppression of certain types ofnerve signals. Dextromethorphan also acts at another class of receptorsknown as N-methyl-D-aspartate (NMDA) receptors, which are one type ofexcitatory amino acid (EAA) receptor. Unlike its agonist activity atsigma receptors, DM acts as an antagonist at NMDA receptors, which meansthat DM suppresses the transmission of nerve impulses mediated via NMDAreceptors. Since NMDA receptors are excitatory receptors, the activityof DM as an NMDA antagonist also leads to the suppression of certaintypes of nerve signals. The anti-excitotoxic activity ofdextromethorphan and dextrorphan, and the blockade of NMDA receptors bythese drugs, are discussed in items such as Choi 1987, Wong et al 1988,Steinberg et al 1988, and U.S. Pat. No. 4,806,543 (Choi 1989).Dextromethorphan has also been reported to suppress activity at neuronalcalcium channels (Carpenter et al 1988). Dextromethorphan and thereceptors it interacts with are further discussed in Tortella et al1989, Leander 1989, Koyuncuoglu & Saydam 1990, Ferkany et al 1988,George et al 1988, Prince & Feeser 1988, Feeser et al 1988, Craviso andMusacchio 1983, and Musacchio et al 1988.

DM disappears fairly rapidly from the bloodstream (see, e.g., Vetticadenet al 1989 and Ramachander et al 1977). DM is converted in the liver totwo metabolites called dextrorphan and 3-methoxymorphinan, by anenzymatic process called O-demethylation. This enzyme is usuallyreferred to as debrisoquin hydroxylase, since it was discovered a numberof years ago to carry out a hydroxylation reaction on debrisoquin. It isalso referred to in various articles as P450DB or P450-2D6. A number ofcompounds inhibit the activity of the debrisoquin hydroxylase (sparteinemonooxygenase) isozyme; see Inaba et al 1985. The most powerful of theseinhibitors is quinidine, a dextrorotatory stereoisomer of quinine; it isnormally used to treat cardiac arrhythmias. Inaba et al 1986 and Nielsenet al 1990 discuss the ability of quinidine to inhibit the oxidation ofsparteine in in vivo animal tests, and Brinn et al 1986, Brosen et al1987, and Broly et al 1989 discuss the ability of quinidine to inhibitDM metabolism in liver cell preparations. In addition to the inhibitionof debrisoquin hydroxylase, which is exceptionally potent and easilydemonstrated, other cytochrome P450 isozymes are also likely to besuppressed by quinidine, with varying levels of binding affinity.Accordingly, even though quinidine exerts its most marked effect ondebrisoquin hydroxylase, it is likely to suppress a number of othercytochrome P450 enzymes as well, thereby subjecting a patient to a moregeneral loss of normal and desirable liver activity. The primaryoxidized metabolic product of dextromethorphan is dextrorphan, which iswidely believed among neurologists to be active in exactly the samemanner as dextromethorphan; both drugs reportedly are sigma agonists,NMDA antagonists, and calcium channel antagonists. It has been shownthat the administration of a compound which inhibits debrisoquinhydroxylase, in conjunction with DM, causes a major increase in theconcentration and stability of DM in the blood of patients, compared topatients who receive only DM; and the administration of a debrisoquinhydroxylase inhibitor in conjunction with DM has a clear and substantialimpact on the detectable effects of DM in humans. Even thoughdebrisoquin hydroxylase inhibitors are preferred in the potentiatingactivity of Dextromethorphan, other agents which inhibit the oxidativeactivity of cytochrome-P450, such as a naphthyridine, xanthine, phenoxyamino alkane, carbamoyl imidazole, guanidine imidazole, e.g. cimetidine(N-cyano-N′-methyl-N″-[2[[(5-methyl-1H-imidazol-4yl)methyl]thio]ethyl]guanidine), quinoline, e.g. chloroquine(7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline) and primaquine(8-(4-amino-1-methylbutylamino)-6-methoxyquinoline), a trifluoromethyloxime ether, e.g., fluvoxamine, also known as5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1 pentanone 0-(2-aminoethyl)oxime may be useful in potentiating the activity of dextromethorphan.

Caffeine is present in several analgesic preparations. To the extentthat this is at all rational it may be related to the presence ofadenosine A_(2A) receptors in or close to sensory nerve endings thatcause hyperalgesia (Ledent et al., 1997). Indeed, caffeine does havehypoalgesic effects in certain types of C-fiber-mediated pain (Myers etal., 1997). The analgesic effects are small (Bättig and Welzl, 1993).Caffeine could have an indirect beneficial effect by elevating mood andclear-headedness (Lieberman et al., 1987). In this study it was foundthat both mood and vigilance were more improved by aspirin incombination with caffeine than by aspirin given alone or by placebo.

As reviewed (Migliardi et al., 1994), patients rate caffeine-containinganalgesics as superior to caffeine-free preparations for the treatmentof headache. In addition, caffeine may exert an antinociceptive effectin the brain, because it can antagonize pain-related behavior in themouse following i.c.v. injection (Ghelardini et al., 1997). Moreover,this effect may be related to antagonism of a tonic inhibitory activityof adenosine A₁ receptors that reduce cholinergic transmission (Rainnieet al., 1994; Carter et al., 1995).

As noted above, sleep seems to be one of the physiological functionsmost sensitive to the effects of caffeine in humans. It is well knownthat caffeine taken at bedtime affects sleep negatively (see Snel,1993). Generally, more than 200 mg of caffeine is needed to affect sleepsignificantly. The most prominent effects are shortened total sleeptime, prolonged sleep latency, increases of the initial light sleep EEGstages, and decreases of the later deep sleep EEG stages, as well asincreases of the number of shifts between sleep stages.

In order to practice the invention, a non-limiting list of μ-opiateanalgesic drugs which may be utilized in the present invention includetramadol, metabolites thereof, salts thereof, complexes thereof.

NMDA antagonists which may be utilized in the present invention includedextromethorphan, ketamine and amantidine, as well as metabolites, saltsand complexes thereof.

A non-limiting list of caffeine analogs which may be used in the presentinvention include xanthine, hypoxanthine (6-hydroxypurine),1-methylxanthine, 3-methylxanthine, 7-methylxanthine, azaxanthine(8-aza-2,6-dihydroxypurine), theophylline and theobromine.

Oral combination dosage units preferably contain dextromethorphan in therange of about 30 to not more than 200 milligrams (mg), preferably inthe range of about 60 and about 120 mg and of tramadol in the range ofabout 30 to about 500 mg, preferably in the range of about 30 to about200 mg, so long as the combined dose received by the patient isaccompanied by minimal or substantially no undesirable side effects.Caffeine may be included in the composition at a dosage of about 30 tonot more than 200 mg, preferably in the range of about 60 mg and about100 mg.

A particularly preferred oral combination dosage unit contains about 120mg dextromethorphan and not more than 100 mg tramadol, more preferablyabout 90 mg dextromethorphan and not more than about 100 mg tramadol.Another preferred oral combination dosage unit contains about 120 mgdextromethorphan, about 100 mg of caffeine and not more than 100 mgtramadol, more preferably about 90 mg dextromethorphan, about 60 mg ofcaffeine and not more than about 100 mg tramadol.

Alternatively, the dextromethorphan and tramadol may be formulatedseparately in the foregoing compositions as the sole active ingredientfor practicing sequential administration of each respective drug.

Alternatively, the dextromethorphan, caffeine and tramadol may beformulated separately in the foregoing compositions as the sole activeingredient for practicing sequential administration of each respectivedrug.

For sequential administration therapy, tramadol, caffeine anddextromethorphan each is administered in a separate dosage. Forsequential administration of tramadol, the dosage unit preferablycontains tramadol in a range of about 10 to about 500 mg, morepreferably in the range of about 20 mg to about 300 mg, foradministration of caffeine, the dosage unit preferably contains caffeinein a range of about 10 to about 400 mg, more preferably in the range ofabout 30 mg to about 200 mg and for administration of dextromethorphanthe dosage unit preferably contains dextromethorphan in a range of about30 to not more than 120 mg, more preferably in the range of about 60 toabout 90 mg so long as the total combined dose received by the patientis accompanied by minimal or substantially no undesirable side effects.

A particularly preferred sequential administration dosage unit containstramadol in the range of about 30 to about 100 mg and ofdextromethorphan contains dextromethorphan in the range of about 30 toabout 135 mg. Preferably, each drug is administered orally.Alternatively, each drug can be administered by different oral routes;i.e., one can be ingested and the other administered sublingually or bybuccal patch.

For effective sequential administration of tramadol, caffeine anddextromethorphan, the release of each drug is preferably staggered tomaximize the beneficial delayed ejaculation by dextromethorphan.

A particularly preferred sequential administration dosage unit containstramadol in the range of about 30 to about 100 mg, caffeine in the rangeof 30 to 100 mg and dextromethorphan in the range of about 30 to about135 mg. Preferably, each drug is administered orally. Alternatively,each drug can be administered by different oral routes; i.e., one can beingested and the other administered sublingually or by buccal patch.

For effective sequential administration of tramadol, caffeine anddextromethorphan, the release of each drug is preferably staggered tomaximize the beneficial delayed ejaculation by dextromethorphan.

In order to potentiate the effect of dextromethorphan, optionally aneffective amount of a cytochrome P450 enzyme inhibitor such as quinidinecan be administered to the patient either in a combination dosage unitor in a sequential administration dosage unit. When a cytochrome P450inhibitor is administered in order to augment the effect ofdextromethorphan, the dosage of dextromethorphan can be suitablyadjusted to have maximum efficacy with minimum side effects. Oralcombination dosage units preferably can contain quinidine in the rangeof about 50 to not more than 200 milligrams (mg), preferably in therange of from about 90 to about 120 mg.

Active Agents for Treating Premature Ejaculation in CLASS II Males

In order to carry out the method of the invention to treat prematureejaculation in CLASS II males who have erection as well as ejaculationproblems, selected pharmacologically active agent is administered to anindividual. The active agents may be administered orally, parenterally,buccally, rectally, or locally by intracavernosal injection or bydelivery to the urethra. Suitable pharmacologically active agentsinclude, cyclic-GMP-specific phosphodiesterase type 5 (PDE5) inhibitorssuch as sildenafil, caffeine, anti-excitotoxic agents such asdextromethorphan, a μ-opiate analgesic such as tramadol and optionallythe cytochrome-P450 inhibitors such as quinine, quinidine,naphthyridine, xanthine, phenoxy amino alkane, carbamoyl imidazole,guanidine imidazole, e.g. cimetidine(N-cyano-N′-methyl-N″-[2[[(5-methyl-1H-imidazol-4yl)methyl]thio]ethyl]guanidine), quinoline, e.g. chloroquine(7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline) and primaquine(8-(4-amino-1-methylbutylamino)-6-methoxyquinoline), a trifluoromethyloxime ether, e.g., fluvoxamine, also known as5-methoxy-1-[4-(trifluoromethyl)-phenyl]-1 pentanone 0-(2-aminoethyl)oxime.

Sildenafil is designated chemically as1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine and has the following structural formula: FIG. 3

Sildenafil citrate is presently the active ingredient of a commercialmedication for impotence sold under the designation Viagra™ (PfizerLabs, N.Y.) formulated in tablets equivalent to 25 mg, 50 mg and 100 mgsildenafil for oral administration. According to the manufacturer, inaddition to the active ingredient, sildenafil citrate, each tabletcontains the following inactive ingredients: microcrystalline cellulose,anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesiumstearate, hydroxypropyl methylcellulose, titanium dioxide, lactose,triacetin, and FD&C Blue #2 aluminum lake.

It is known from in vitro studies that sildenafil is approximately 4,000fold more selective for inhibiting phosphodiesterase type 5 (PDE5) thanon other known phosphodiesterases, such as PDE3, which is involved incontrol of cardiac contractility. Sildenafil is reportedly only about10-fold as potent for PDE5 compared to PDE6, an enzyme found in theretina and it is this lower selectivity which is thought to be the basisfor abnormalities related to color vision observed with higher doses orplasma levels.

Sildenafil, administered as the commercially available Viagra™formulation, is reported to be rapidly absorbed after oraladministration, with absolute bioavailability of about 40%. Itspharmacokinetics are dose-proportional over the recommended dose range.Based on the Viagra™ manufacturer's product literature, maximum observedplasma concentrations are reached within 30 to 120 minutes (median 60minutes) of oral dosing in the fasted state. When the Viagra™formulation is taken with a high fat meal, the rate of absorption isreduced, with a mean delay in Tmax of 60 minutes and mean reduction inCmax of 29%. The mean steady state volume of distribution (Vss) forsildenafil is reportedly 105 L, indicating distribution into thetissues. Based upon reported measurements of sildenafil in the semen ofhealthy volunteers 90 minutes after dosing, less than 0.001% of theadministered dose appeared in the semen of the patients.

Surprisingly, a therapeutically effective dosage combination ofdextromethorphan, tramadol and sildenafil employed with the compositionsof this invention maximizes the beneficial erectogenic efficacy ofsildenafil by delaying the premature ejaculation.

Oral combination dosage units preferably contain dextromethorphan in therange of about 10 to not more than 300 milligrams (mg), preferably inthe range of about 30 and about 200 mg, tramadol in the range of about10 to not more than 200 milligrams (mg), preferably in the range ofabout 30 and about 150 mg and of sildenafil in the range of about 10 toabout 150 mg, preferably in the range of about 15 to about 100 mg, solong as the combined dose received by the patient is accompanied byminimal or substantially no undesirable side effects. A particularlypreferred oral combination dosage unit contains about 150 mgdextromethorphan, not more than 200 mg of tramadol, more preferablyabout 100 mg of tramadol and not more than 150 mg sildenafil, morepreferably about 135 mg dextromethorphan, about 100 mg of tramadol andnot more than about 100 mg sildenafil.

Alternatively, the dextromethorphan, tramadol and sildenafil may beformulated separately in the foregoing compositions as the sole activeingredient for practicing sequential administration of each respectivedrug.

For sequential administration therapy, sildenafil, tramadol anddextromethorphan each is administered in a separate dosage. Forsequential administration of sildenafil, the dosage unit preferablycontains sildenafil in a range of about 10 to about 300 mg, morepreferably in the range of about 25 to about 200 mg, for administrationof tramadol, the dosage unit preferably contains tramadol in a range ofabout 20 to not more than 400 mg, more preferably in the range of about30 to about 200 mg and for administration of dextromethorphan the dosageunit preferably contains dextromethorphan in a range of about 30 to notmore than 500 mg, more preferably in the range of about 60 to about 300mg so long as the total combined dose received by the patient isaccompanied by minimal or substantially no undesirable side effects.

A particularly preferred sequential administration dosage unit ofsildenafil contains sildenafil in the range of about 50 to about 150 mg,of tramadol contains tramadol in the range of about 50 to about 200 mgand of dextromethorphan contains dextromethorphan in the range of about45 to about 200 mg. Preferably, each drug is administered orally.Alternatively, each drug can be administered by different oral routes;i.e., one can be ingested and the other administered sublingually or bybuccal patch.

If desired, to facilitate absorption and thus bioavailability,absorption enhancing agents, such as cyclodextrins, particularlyβ-cyclodextrin, or a derivative thereof, such ashydroxypropyl-β-cyclodextrin (HPBCD) and the like may be included.Cyclodextrins are a group of cyclic, nonreducing oligosaccharides builtup from six, seven or eight glucopyranose rings, respectively known asalpha, beta and gamma cyclodextrins. The cyclodextrins are a class ofcavity-containing cyclic compounds possessing the property of forming amolecular inclusion complexes, which anchor or entrap another chemicalcompounds without the formation of covalent bonds. HPBCD is a cyclicpolymer having a doughnut-shaped molecular structure including an innercavity.

Hydroxypropyl-β-cyclodextrins are commercially available compounds thatare derived from β-cyclodextrins by condensation with a propylene oxideto provide the corresponding hydroxypropyl derivatives having a degreeof substitution (D.S.) of up to about 15 or higher. For the purposes ofthe present invention a D.S. value of about 5 to 7 is preferred.

The preparation of such suitable hydroxypropyl-β-cyclodextrins isdescribed, inter alia, in the International Journal of Pharmaceutics,29, 73-82 (1986) and in the Journal of Pharmaceutical Sciences, 75 (6),571-572 (1986). Also known and suitable for the present invention arethe hydroxypropyl-β-cyclodextrins that are polyethers of cyclodextrinsand are obtained by the condensation of an excess of hydroxypropyleneoxide with β-cyclodextrin as described in U.S. Pat. No. 3,459,731, toGramera et al. Hydroxypropyl-β-cyclodextrin (HPBCD) is particularlypreferred cyclodextrin constituent, but is not limited thereto. Theweight percent of the HPBCD in the composition is preferably in therange of about 1 to about 10 weight percent of the total composition.

Particularly in the case of sildenafil, it has been found that HPBCDenhances bioavailability. Thus, the desired therapeutic effect can beachieved with a relatively lower dose of sildenafil, thereby minimizingthe likelihood of adverse affects.

For effective sequential administration of sildenafil, tramadol anddextromethorphan, the release of each drug is preferably staggered tomaximize the beneficial prolongation of erection by dextromethorphan andtramadol and maintenance of erection by sildenafil upon sexualstimulation.

To augment the beneficial effect of dextromethorphan, tramadol andsildenafil therapy, lesser amounts of erectogenic agents can beincluded. The term “erectogenic agents” as used herein refers to adrenalsteroids, such as testosterone, dehydroepiandrosterone (DHEA) and thelike. Preferably, the erectogenic agents are added in an amount in therange of about 5 to about 10 percent by weight, more preferably in therange of about 6 to about 8 percent by weight of the weight ofsildenafil administered.

To offset the drowsiness or sedation experienced by some of the users ofopiate analgesic, caffeine can be added in the composition.

In order to potentiate the effect of dextromethorphan, optionally aneffective amount of a cytochrome P450 enzyme inhibitor such as quinidinecan be administered to the patient either in a combination dosage unitor in a sequential administration dosage unit. When a cytochrome P450inhibitor is administered in order to augment the effect ofdextromethorphan, the dosage of dextromethorphan can be suitablyadjusted to have maximum efficacy with minimum side effects. Oralcombination dosage units preferably can contain quinidine in the rangeof about 50 to not more than 200 milligrams (mg), preferably in therange of about 90 and about 120 mg. Oral combination dosage unitspreferably can contain quinidine in the range of about 50 to not morethan 200 milligrams (mg), preferably in the range of about 90 and about120 mg.

The active agents may be administered in the form of pharmaceuticallyacceptable salts, esters, amides or prodrugs or combinations thereof.However, conversion of inactive ester, amide or prodrug forms to anactive form must occur prior to or upon reaching the target tissue orcell. Salts, esters, amides and prodrugs of the active agents may beprepared using standard procedures known to those skilled in the art ofsynthetic organic chemistry and described, for example, by J. March,Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed.(New York: Wiley-Interscience, 1992). For example, acid addition saltsare prepared from the free base (typically wherein the neutral form ofthe drug has a neutral—NH2 group) using conventional means, involvingreaction with a suitable acid. Generally, the base form of the drug isdissolved in a polar organic solvent such as methanol or ethanol and theacid is added thereto. The resulting salt either precipitates or may bebrought out of solution by addition of a less polar solvent. Suitableacids for preparing acid addition salts include both organic acids,e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, malic acid, malonic acid, succinic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid,salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. An acid addition salt may be reconvertedto the free base by treatment with a suitable base. Conversely,preparation of basic salts of acid moieties which may be present on adrug are prepared in a similar manner using a pharmaceuticallyacceptable base such as sodium hydroxide, potassium hydroxide, ammoniumhydroxide, calcium hydroxide, trimethylamine, or the like. Preparationof esters involves functionalization of hydroxyl and/or carboxyl groupswhich may be present within the molecular structure of the drug. Theesters are typically acyl-substituted derivatives of free alcoholgroups, i.e., moieties which are derived from carboxylic acids of theformula RCOOH where R is alkyl, and preferably is lower alkyl. Esterscan be reconverted to the free acids, if desired, by using conventionalhydrogenolysis or hydrolysis procedures. Preparation of amides andprodrugs can be carried out in an analogous manner. Other derivativesand analogs of the active agents may be prepared using standardtechniques known to those skilled in the art of synthetic organicchemistry, or may be deduced by reference to the pertinent literature.In addition, chiral active agents may be in enantiomerically pure form,or they may be administered as an enantiomeric mixture.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drugs in combination with a pharmaceutically acceptable carrierand, in addition, may include other pharmaceutical agents, adjuvants,diluents, buffers, etc. The compounds may thus be administered orally,parenterally, transdermally, rectally, nasally, buccally, topically orvia an implanted reservoir in dosage formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term “parenteral” as used herein is intended toinclude subcutaneous, intravenous, and intramuscular injection. Theamount of active compound administered will, of course, be dependent onthe subject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc., an active compound as described herein and optional pharmaceuticaladjuvants in an excipient, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of nontoxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan mono-laurate,triethanolamine sodium acetate, triethanolamine oleate, etc. Actualmethods of preparing such dosage forms are known, or will be apparent,to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, referenced above. For oral administration, thecomposition will generally take the form of a tablet or capsule, or maybe an aqueous or nonaqueous solution, suspension or syrup. Tablets andcapsules are preferred oral administration forms. Tablets and capsulesfor oral use will generally include one or more commonly used carrierssuch as lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. When liquid suspensions are used,the active agent may be combined with emulsifying and suspending agents.If desired, flavoring, coloring and/or sweetening agents may be added aswell. Other optional components for incorporation into an oralformulation herein include, but are not limited to, preservatives,suspending agents, thickening agents, and the like.

Parenteral administration, if used, is generally characterized byinjection. Injectable formulations can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solubilization or suspension in liquid prior to injection, or asemulsions. Preferably, sterile injectable suspensions are formulatedaccording to techniques known in the art using suitable carriers,dispersing or wetting agents and suspending agents. The sterileinjectable formulation may also be a sterile injectable solution or asuspension in a nontoxic parenterally acceptable diluent or solvent.Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils, fatty esters or polyols areconventionally employed as solvents or suspending media. A more recentlyrevised approach for parenteral administration involves use of a slowrelease or sustained release system, such that a constant level ofdosage is maintained. See, e.g., U.S. Pat. No. 3,710,795.

The active agent can be administered in a pharmaceutical formulationsuitable for transurethral drug delivery. The formulation contains oneor more selected carriers or excipients, such as water, silicone, waxes,petroleum jelly, polyethylene glycol (“PEG”), propylene glycol (“PG”),liposomes, sugars such as mannitol and lactose, and/or a variety ofother materials, with polyethylene glycol and derivatives thereofparticularly preferred. Depending on the drug administered, it may bedesirable to incorporate a transurethral permeation enhancer in theurethral dosage form. Examples of suitable transurethral permeationenhancers include dimethylsulfoxide (“DMSO”), dimethyl formamide(“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide (“C10MSO”), polyethylene glycol monolaurate (“PEGML”), glycerol monolaurate,lecithin, the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Nelson Research & Development Co. Irvine, Calif.), SEPA®(available from Macrochem Co., Lexington, Mass.), alcohols (e.g.,ethanol), detergents (such as Tergitol®, Nonoxynol-9® and TWEEN-80®) andthe like.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples which follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLE 1 Capsule Formulations

The following ingredients in each one of the capsule formulations wereweighed accurately, ground using a pestle and mortar to fine andhomogeneous powders. These powders were sieved through 100 mesh andfilled into hard gelatin capsules. The composition of each capsuleformulation is listed below.

In each In 100 Capsule Formulation 1 Dextromethorphan 30 mg 3.0 gTramadol Hydrochloride 15 mg 1.5 g Starch (potato) 50 mg 5.0 g MannitolUSP 40 mg 4.0 g Microcrystalline Cellulose^(a) 50 mg 5.0 g Stearic acid10 mg 1.0 g Silica gel  5 mg 0.5 g Total Solid 200 mg  20.0 g  CapsuleFormulation 2 Dextromethorphan 45 mg 4.5 g Tramadol Hydrochloride 20 mg2.0 g Starch (potato) 60 mg 6.0 g Mannitol USP 50 mg 5.0 gMicrocrystalline Cellulose^(a) 50 mg 5.0 g Stearic acid 10 mg 1.0 gSilica gel  5 mg 0.5 g Total Solid 250 mg  25.0 g  Capsule Formulation 3Dextromethorphan 45 mg 4.5 g Tramadol Hydrochloride 25 mg 2.5 g CaffeineUSP 30 mg 3.0 g Starch (potato) 50 mg 5.0 g Sucrose USP 40 mg 4.0 gMicrocrystalline Cellulose^(a) 40 mg 4.0 g Stearic acid  5 mg 0.5 gSilica gel  5 mg 0.5 g Total Solid 250 mg  25.0 g 

EXAMPLE 2 Capsule Formulations Containing Sildenafil

The following ingredients in each one of the capsule formulations wereweighed accurately, ground using a pestle and mortar to fine andhomogeneous powders. These powders were sieved through 100 mesh andfilled into hard gelatin capsules. The composition of each capsuleformulation is listed below.

In each In 100 Capsule Formulation 1 Sildenafil Citrate 25 mg 2.5 gDextromethorphan 45 mg 4.5 g Tramadol Hydrochloride 20 mg 2.0 g Starch(potato) 60 mg 6.0 g Mannitol USP 50 mg 5.0 g MicrocrystallineCellulose^(a) 48 mg 4.8 g Stearic acid 10 mg 1.0 g Silica gel  2 mg 0.2g Total Solid 250 mg  25.0 g  Capsule Formulation 2 Sildenafil Citrate25 mg 2.5 g Dextromethorphan 30 mg 3.0 g Tramadol Hydrochloride 15 mg1.5 g Starch (potato) 60 mg 6.0 g Mannitol USP 50 mg 5.0 gMicrocrystalline Cellulose^(a) 58 mg 5.8 g Stearic acid 10 mg 1.0 gSilica gel  2 mg 0.2 g Total Solid 250 mg  25.0 g  Capsule Formulation 3Sildenafil Citrate 25 mg 2.5 g Dextromethorphan 45 mg 4.5 g TramadolHydrochloride 25 mg 2.5 g Caffeine 30 mg 3.0 g Starch (potato) 60 mg 6.0g Sucrose USP 65 mg 6.5 g Microcrystalline Cellulose^(a) 58 mg 5.8 gStearic acid 10 mg 1.0 g Silica gel  7 mg 0.7 g Total Solid 325 mg  32.5g 

EXAMPLE 3

The subject was a 40 year old white male in good health. The subject hadexpressed satisfaction with his sexual activity but desired additional‘staying power’. The subject took two capsules of the test article, thecapsule formulation 1 in example 2, approximately 1 hour before engagingin sexual activity. The subject reported that he was able to delay hisclimax by merely exerting his will. He related that he was able tocontinue intercourse for as long as he was physically able to performthe necessary motions.

EXAMPLE 4

The subject was a 31 year old white male in excellent health. Thesubject took two capsules of the test article, the capsule formulation 2in example 1, approximately three hours before commencing sexualactivity. The subject reported that his stamina was significantlyincreased and that he had achieved two climaxes without an interveningflaccid period.

EXAMPLE 5

A white male of 49 years old was in the process of establishing abusiness and manufacturing several products, making strategy forsecuring capital for the company and marketing the product. He used towork long hours a day. He noticed that during sexual activities with hisgirl friend he could not control the ejaculation resulting indisappointment from his female partner. Because of the prematureejaculation problem he was trying to avoid sexual contact with hisfemale partner whenever possible and his partner was feeling unfulfilledsexual experience and sometimes anger. The patient was provided withcapsules of formulation 1 in example 2 and advised to take 2 capsuleapproximately 3 hours before intercourse and 1 capsule approximately 1hour before intercourse. He took 2 capsules in the first night andaccording to his testimony, he felt slightly numb in his penis and hewas able to arouse his female partner's sexual feelings by performingpre-intercourse sexual conducts and his partner was able to performpre-intercourse sexual conducts with his penis for almost half hourwithout any ejaculation. He was able to perform intercourse for morethan 20 minutes and his partner felt exhaustion. His female partner wasso ecstatic and he was able to perform sexual intercourse 2 times thatnight. The patient is periodically taking the capsules whenever he wantsto have a good and sound sexual intercourse for his otherwise stressfulbody.

EXAMPLE 6

A white male of 40 yrs old who is living with his girl friend was keenlyinterested in the effect of the compositions of the present invention onhis sexual activity. The subject consumed two capsule described asformulation 1 in example 2 at approximately 18:00. At 18:45 the subjectreported a feeling of heaviness in the genitals with a slight feeling offlushing in the face. Sexual activity commenced at 19:15. Subjectreported that his erection had a greater degree of stiffness and a senseof increased distension over that usually experienced. The subjectreported that his staying power was increased by approximately 70% overhis usual experience. Sexual intercourse was continued for approximately90 minutes concluding with a more powerful than usual orgasm.

EXAMPLE 7 The Effect of Sildenafil, Dextromethorphan and Tramadol onCLASS II Males

In order to demonstrate the efficacy of sildenafil, tramadol anddextromethorphan composition to treat premature ejaculation on CLASS IImales, 30 volunteers have been chosen from the age groups of 21 and 57who had premature ejaculation and erection problems. The volunteers weregiven capsules of formulation 1 in example 2. The volunteers were askedto take 2 capsules 2-3 hours before the sexual act and were asked tofill out the form provided in Table before and after the sexual acts.The study was conducted for 8 weeks and the results were compiled andanalyzed for sexual satisfaction. The results show that more than 80% ofthe volunteers were extremely satisfied with the composition of theinvention for pre-mature ejaculation problems.

The following publications are incorporated in pertinent part byreference herein.

REFERENCES

-   1. Albers, G W et al, “Safety and tolerance of oral dextromethorphan    in patients at risk for brain ischemia,” Stroke 22: 1075-1077    (1991).-   2. Applebaum, J S et al, “Dextromethorphan in the treatment of ALS:    A pilot study,” Abstract number 960S (page 393) in Neurology 41    (Suppl, 1), March 1991-   3. Balon, “Antidepressants in the Treatment of Premature    Ejaculation,” Journal of Sex & Marital Therapy, 22(2):85-96 (1996).-   4. Brinn R et al, “Sparteine oxidation is practically abolished in    quinidine-treated patients,” Br. J. Clin. Pharmacol. 22: 194-197    (1986).-   5. Broly F et al, “Effect of quinidine on the dextromethorphan    O-methylase activity of microsomal fractions from human liver,”    Br. J. Clin. Pharmacol. 28: 29-36 (1989).-   6. Broly F et al, “Inhibitory studies of mexiletine and    dextromethorphan oxidation in human liver microsomes,” Biochem.    Pharmacol. 39: 1045-1053 (1990).-   7. Brosen K et al, “Extensive metabolizers of debrisoquin become    poor metabolizers during quinidine treatment,” Pharmacol. Toxicol.    60: 312-314 (1987)-   8. Carpenter, C L et al, “Dextromethorphan and dextrorphan as    calcium channel antagonists,” Brain Research 439: 372-375 (1988)-   9. Cavallini (1995) “Alpha-1 Blockade Pharmacotherapy in Primitive    Psychogenic Premature Ejaculation Resistant to Psychotherapy,” Eur.    Urology 28:126-130.-   10. Choi D W, “Dextrorphan and dextromethorphan attenuate glutamate    neurotoxicity,” Brain Res. 402: 333-336 (1987)-   11. Craviso G L and Musacchio J M, “High affinity dextromethorphan    binding sites in guinea pig brain,” Mol. Pharmacol. 23: 619-640    (1983).-   12. David J E et al., “Identification of 6′,7′-Dihydroxybergamottin,    a Cytochrome P450 Inhibitor, In Grapefruit Juice”, Drug Metabolisms    and Disposition, vol. 24, No. 12, pp. 1287-1290 (1996).-   13. Dayer R et al, “Dextromethorphan O-demethylation in liver    microsomes . . . ” Clin. Pharmacol. Ther. 45: 34-40 (1989)-   14. Feeser et al, Neurosci. Letters 86: 340-345 (1988)-   15. Di Silverio et al. (1996), “Effects Compares de l'Incision    Cervico-Prostatique (ICP) et de l'Association ICP et Agonistes de la    LHRH dans le Traitement de l'Hypertrophie Benigne de la Prostate,”    Journal D'Urologie 102(3):111-116.-   16. Falaschi et al. (1981), “Brain Dopamine and Premature    Ejaculation: Results of Treatment with Dopamine Antagonists,”    Apomorphine and Other Dopaminomitics 1:117-121.-   17. Feinberg (1991), “Clomipramine for Obsessive-Compulsive    Disorder,” AFP Clinical Pharmacology 43(5):1735-1738.-   18. Ferkany et al, Eur. J. Pharmacol. 151: 151-154(1988)-   19. Ferrari et al (1994), “The Selective D2 Dopamine Receptor    Antogonist Eticlopride Counteracts the Ejaculatio Praecox Induced by    the Selective D2 Dopamine Agonist SND 919 in the Rat,” Life Sciences    55(14):1155-1162. (8 pages)-   20. Fonne-Pfister et al, Biochem. Biophys. Res. Communic. 148:    1144-1150 (1987)-   21. Frank H B et al., “Synthesis and Biological Evaluation of    6′,7′-Dihydroxybergamottin (6,7-DHB), A Naturally Occurring    Inhibitor of Cytochrome P450 3A4”, Biorganic & Medicinal Chemistry    Letter, vol. 7, No. 20, pp. 2593-2598, 1997.-   22. Guttendorf R J et al, “Simplified phenotyping with    dextromethorphan by thin-layer chromatography,” Ther. Drug. Monit.    10: 490-498 (1988).-   23. Hull et al. (1994), “The Roles of Nitric Oxide in Sexual    Function of Male Rats,” Neuropharmacology 33 (11): 1499-1504.-   24. Goldstein et al., “Oral Sildenafil in the Treatment of Erectile    Dysfunction,” The New England Journal of Medicine, 338, pp 1397-1404    (1998).-   25. Inaba T et al, “In vitro inhibition studies of two isozymes of    human liver cytochrome P-450,” Drug Metabolism and Disposition 13:    443-447 (1985)-   26. Inaba T et al, “Quinidine: Potent inhibition of sparteine and    debrisoquin oxidation in vivo,” Br. J. Clin. Pharmacol. 22: 199-200    (1986)-   27. Inaba T et al, “Quinidine: Potent inhibition of sparteine and    debrisoquin oxidation in vivo,” Br. J. Clin. Pharmacol. 22: 199-200    (1986).-   28. Rashid J et al., “Quercetin, an in vitro inhibitor of CYP3A,    does not contribute to the interaction between nifedipine and    grapefruit juice”, Br J clin Pharmac, vol. 36, pp. 460-463, 1993.-   29. Jachau M R “Substrates, Specificities and Functions of the P450    Cytochromes”, LIFE SCIENCES, Vol. 47, pp. 2385-2394 (1990).-   30. Neal J J et al., “Inhibition of Insect Cytochromes P450 by    Furanocoumarins”, 1994, Pesticide Biochemistry and Physiology 50,    pp. 43-50.-   31. Jerzy Klinger (2000) “Vita Sexualis: The truth about human sex    life”, By Klinger, Pawel, Translated from Polish to English by    Klinger, Jerzy, Copyright© 1994 pages 1-362.-   32. Kan He et al., “Inactivation of Cytochrome P450 3A4 by    Bergamottin, a Component of Grapefruit Juice”, Chem. Res. Toxicol,    vol. 11, pp. 252-259, 1998.-   33. Katsuyuki Fukuda, et al., “Grapefruit Component Interacting with    Rat and Human P450 CYP3A: Possible Involvement of Non-Flavenoid    Components in Drug Interaction”, Biol. Pharm. Bull., vol. 20, No. 5,    pp. 560-564, May 1997.-   34. Koppel C et al, “Urinary metabolism of dextromethorphan in man,”    Arzneim.-Forsch./Drug Research 37: 1304-1306 (1987).-   35. Koyuncuoglu & Saydam, Intnl. J. Clin. Pharmacol. Ther. Tox. 28:    147-152 (1990)-   36. Kupfer A et al “Dextromethorphan as a safe probe for    debrisoquine hydroxylation polymorphism,” Lancet ii: 517-518 (1984).-   37. Leander, Epilepsy Res. 4: 28-33 (1989)-   38. Bourian M et al., “Coumarin Derivatives in Grapefruit Juice and    Their Interactions with Mammalian Drug Metabolising Enzyme Systems”,    Annual Congress on Medicinal Plant Research, vol. 44, pp. 43, 1996.-   39. Obermeier M T et al., “Effects of bioflavonoids on hepatic P450    activities”, Xeonbiotica, vol. 25, No. 6, pp. 575-584, 1995.-   40. Marina Tinel, et al., “Inactivation of Human Liver Cytochrome    P-450 by the Drug Methoxsalen and Other Psoralen Derivatives”,    Biochemical Pharmacology, vol. 36, No. 6, pp. 951-955, 1987.-   41. Metz et al. (1997), “Premature Ejaculation: A    Psychophysiological Review,” Journal of Sex & Marital Therapy    23(1):3-23.-   42. Musacchio J M et al, “High affinity dextromethorphan binding    sites in the guinea pig brain,” J. Pharmacol. Exp. Ther. 247:    424-431 (1988)-   43. Napoli-Farris et al. (1984), “Stimulation of Dopamine    Autoreceptors Elicits Premature Ejaculation in Rats,” Pharmacology    Biochemistry & Behavior 20:69-72.-   44. Nielsen M D et al, “A dose-effect study of the in vivo    inhibitory effect of quinidine on sparteine oxidation in man,”    Br. J. Clin. Pharmacol. 29: 299-304 (1990).-   45. Niznik et al, Arch. Biochem. Biophys. 26: 424-432 (1990)-   46. Physician's Desk Reference, 44th Edition (1988), pp. 670-671    (Medical Economics Company, 1990).-   47. Prince & Feeser, Neurosci. Letters 85: 291-296 (1988).-   48. Ramachander G et al, “Determination of dextrorphan in plasma and    evaluation of bioavialability dextromethorphan hydrobromide in    humans,” J Pharm. Sci 66: 1047-1048 (1977)-   49. Rodd E H, Chemistry of Carbon Compounds (Elsevier Publ., New    York, 1960).-   50. Steinberg G K et al, “Delayed treatment with dextromethorphan    and dextrorphan reduces cerebral damage after transient focal    ischemia,” Neurosci Letters 89: 193-197 (1988).-   51. Testa B and Jenner P, “Inhibitors Of Cytochrome P-450s and Their    Mechanism of Action”, DRUG METABOLISM REVIEWS, 12(1)1-117    (1981); F. P. Guengerich, “Cytochrome P450: Advances and Prospects”,    FASEB J., Vol. 6, pp. 667-668 (1992).-   52. Tortella et al, TIPS 10: 501-507 (1989)-   53. Uwe Fuhr et al., “Inhibitory effect of grapefruit juice and its    bitter principal, naringenin, on CYP1A2 dependent metabolism of    caffeine in man*”, Br. J. Clin. Pharmacol., Department of Clinical    Pharmacology, University Hospital. Frankfurt/Main, Germany, vol. 35,    1993, pp 431-436.-   54. Vettican S J et al, “Phenotypic differences in dextromethorphan    metabolism,” Pharmaceut Res. 6: 13-19 (1989)-   55. Waldinger et al. (1997), “Ejaculation-Retarding Properties of    Paroxetine in Patients with Primary Premature Ejaculation: A    Double-Blind, Randomized, Dose-Response Study,” British Journal of    Urology 79:592-595.-   56. Walker E O, and Hunt V P, “An open label trial of    dextromethorphan in Huntington's Disease,” Clin. Neuropharmacol. 12:    322-330 (1989).-   57. Chan W K et al., “Mechanism-Based Inactivation of Human    Cytochrome P450 3A4 by Grapefruit Juice and Red Wine”, Life    Sciences, vol. 62, No. 10, pp. PL 135-142, 1998.-   58. Wong B Y et al, “Dextrorphan and dextromethorphan, common    antitussives, are antiepileptic and antagonize NMDA in brain    slices,” Neurosci Letters 85: 21-26 (1988)-   59. Yingna Cai et al. “Inhibition and Inactivation of Murine Hepatic    Ethoxy- and Pentoxyresorufin O-Delkylase by Naturally Occurring    Coumarins”, Chem. Res. Toxicol, vol. 6, pp. 872-879 (1993).-   60. Brosen K, Murray M and Reidy G F, “Recent Developments In    Hepatic Drug Oxidation Implications For Clinical Pharmacokinetics”,    CLIN. PHARMACOKINET., 18(3): 220-239, 1990.-   61. Murray M and Reidy G F, “Selectivity in the Inhibition of    Mammalian Cytochrome P-450 By Chemical Agents”, PHARMACOLOGICAL    REVIEWS, 42, 85-101 (1990).-   62. Porter T D and Coon M J, “Cytochrome P-450: Multiplicity of    Isoforms, Substrates, and Catalytic and Regulatory Mechanisms”, J.    BIOL. CHEM., Vol. 266, 13469-13472 (1991).-   63. Guengerich F P, “Characterization of Human Microsomal Cytochrome    P-450 Enzymes”, ANNU. REV. PHARMACOL. TOXICOL. Vol, 29, pp. 241-264    (1989).-   64. Martindale, The Extra Pharmacopoeia, 31st edition, pp 333    (London: The Royal Pharmaceutical Society, 1996).-   65. Dayer P, Desmeules J, Collart L. Pharmacology of tramadol Drugs    1997; 53 Suppl 2:18-24.-   66. Raffa R B. A novel approach to the pharmacology of analgesics.    Am J Med 1996; 101(1A):40S-46S.-   67. Reimann W, Hennies H H. Inhibition of spinal noradrenaline    uptake in rats by the centrally acting analgesic tramadol. Biochem    Pharmacol 1994; 47(12):2289-93.-   68. Dayer P, Collart L, Desmeules J. The pharmacology of tramadol.    Drugs 1994; 47 Suppl 1:3-7.-   69. Raffa R B, Friderichs E, Reimann W, Shank R P, Codd E E, Vaught    J L, Jacoby H I, Selve N. Complementary and synergistic    antinociceptive interaction between the enantiomers of tramadol J    Pharmacol Exp Ther 1993; 267: 331-40.-   70. Lee C R, McTavish D, Sorkin E M. Tramadol. A preliminary review    of its pharmacodynamic and pharmacokinetic properties, and    therapeutic potential in acute and chronic pain states. Drugs 1993;    46(2):313-40.-   71. Tobias J D. Seizure after overdose of tramadol. South Med J    1997; 90(8):826-7.-   72. Weinbroum A A, Valery R, Gideon P, Ben-Abraham R. The role of    dextromethorphan in pain control CAN J ANESTH 2000; 47: 585-596.-   73. Rodd E H. Chemistry of Carbon Compounds, Elsevier Publ, New    York, 1960.-   74. Grond S, Thomas M, Detlev Z et al. “Analgesic efficacy and    safety of tramadol enantiomers in comparison with the racemate: a    randomised, double-blind study with gynaecological patients using    intravenous patient-controlled analgesia” Pain 1995; 62(3):313-320.-   75. Shipton E A. “Reviews: Tramadol—Present and Future” Anaesth    Intensive Care 2000; 28:363-374.-   76. Barnung S K, Treschow M, Borgbjerg F M. “Respiratory depression    following oral tramadol in a patient with impaired renal function”    Pain 1997; 71:111-112.-   77. Wiebalck A et al. “Sind Tramadol-Enantiomere für die    postoperative Schmerztherapie besser geeignet als das Racemat? Eine    randomisierte, Plazebo- und Morphin-kontrollierte    Doppelblindstudie”, Der Anaesthesist, 1998; 47: 387-394.-   78. Lintz et al., Arzneim.-Forsch./Drug Res. 1981; 31(11),    1932-1943.-   79. Rajfer J, Aronson W J, Bush P A, Dorey F J, Ignarro L J. Nitric    oxide as a mediator of relaxation of the corpus cavernosum in    response to nonadrenergic, noncholinergic neurotransmission. N.    Eng. S. Med. 1992; 326: 90-4.-   80. Andersson K E, Wagner G. Physiology of the penile erection.    Physiol. Rev. 1995; 75: 191-236.-   81. Burnett A L. The role of nitric oxide in the physiology of an    erection. Biol. Reprod. 1995; 52: 485-9.-   82. Boolell M, Allen M J, Ballard S A, Gepi-Attee S, Muirhead G J,    Naylor A M, Osterloh I H, Gingell J C. Sildenafil: an orally active    type 5 GMP-specific phosphodiesterase inhibitor of penile erection    dysfunction. Int. J. Impot. Res. 1996; 8: 47-52.-   83. Daly J W, Fredholm B B. Caffeine: an atypical drug of    dependence. Drug Alcohol Depend. 1998; 51:199-206.-   84. Nehlig A, Daval J-L, Denry G. Caffeine and the central nervous    system: mechanisms of action, biochemical, metabolic and    psychostimulant effects. Brain Res Brain Res Rev. 1992; 17:139-170.-   85. Fredholm B B, Bättig K, Holmèn J, et al. Actions of caffeine in    the brain with special reference to factors that contribute to its    widespread use. Pharmacol Rev. 1999; 51:83-133.-   86. Ongini E, Fredholm B B. Pharmacology of adenosine A_(2A)    receptors. Trends Pharmacol Sci. 1996; 17:364-372.-   87. Klotz K-N, Hessling J, Hegler J, et al. Comparative pharmacology    of human adenosine receptor subtypes: characterization of stably    transfected receptors in CHO cells. Naunyn Schmiedebergs Arch    Pharmacol. 1998; 357:1-9.-   88. Fredholm B B. Adenosine, adenosine receptors and the actions of    caffeine. Pharmacol Toxicol. 1995; 76:93-101.-   89. Sawynok J. Pharmacological rationale for the clinical use of    caffeine. Drugs. 1995; 49:37-50.-   90. Grobbee D E, Rimm E B, Giovannucci E, et al. Coffee, caffeine,    and cardiovascular disease in men. N Engl J Med. 1990;    323:1026-1032.-   91. Jee S H, He J, Whelton P K, et al. The effect of chronic coffee    drinking on blood pressure: a meta-analysis of controlled clinical    trials. Hypertension. 1999; 33:647-652.-   92. Bättig K and Welzl H (1993) Psychopharmacological profile of    caffeine, in Caffeine, Coffee and Health (Garattini S ed) pp    213-253, Raven Press, New York.-   93. Ledent C, Vaugeois J M, Schiffmann S N, Pedrazzini T, Elyacoubi    M, Vanderhaeghen J J, Costentin J, Heath J K, Vassart G and    Parmentier M (1997) Aggressiveness, hypoalgesia and high blood    pressure in mice lacking the adenosine A2A receptor. Nature 388:    674-678.-   94. Myers D E, Shaikh Z and Zullo T G (1997) Hypoalgesic effect of    caffeine in experimental ischemic muscle contraction pain. Headache    37: 654-658.-   95. Lieberman H R, Wurtman R J, Emde G G and Coviella I L (1987) The    effects of caffeine and aspirin on mood and performance. J Clin    Psychopharmacol 7: 315-320.-   96. Ward N, Whitney C, Avery D and Dunner D (1991) The analgesic    effects of caffeine in headache. Pain 44: 151-155.-   97. Migliardi J R, Armellino J J, Friedman M, Gillings D B and    Beaver W T (1994) Caffeine as an analgesic adjuvant in tension    headache. Clin Pharmacol Ther 56: 576-586.-   98. Ghelardini C, Galeotti N and Bartolini A (1997) Caffeine induces    central cholinergic analgesia. Naunyn-Schmiedebergs Arch Pharmacol    356: 590-595.-   99. Carter A J, O'Connor W T, Carter M J and Ungerstedt U (1995)    Caffeine enhances acetylcholine release in the hippocampus in vivo    by a selective interaction with adenosine A1 receptors. J Pharmacol    Exp Ther 273: 637-642.-   100. Rainnie D G, Grunze H C, McCarley R W and Greene R W (1994)    Adenosine inhibition of mesopontine cholinergic neurons:    Implications for EEG arousal. Science 263: 689-692.-   101. Snel J (1993) Coffee and caffeine: Sleep and wakefulness, in    Coffee, Caffeine and Health (Garattini S ed) pp 255-290, Raven    Press, New York.

The invention claimed is:
 1. A method of effectively treating prematureejaculation in a patient, comprising administering to the patient inneed of such treatment an amount of agents comprising a)dextromethorphan or a pharmaceutically acceptable salt thereof, b)tramadol or a pharmaceutically acceptable salt thereof, and c)sildenafil or a pharmaceutically acceptable salt thereof, whereby thecombined amount of said agents is effective to treat the prematureejaculation in the patient.
 2. The method of claim 1, wherein the agentsare administered separately.
 3. The method of claim 1, wherein theagents are administered in combination.
 4. The method of claim 1,wherein the agents are administered prior to sexual activity.
 5. Themethod of claim 1, wherein the agents are administered orally, by meansof an implant, parenterally, sub-dermally, sublingually, rectally,topically, or via inhalation.
 6. The method of claim 5, wherein theagents are administered orally.
 7. The method of claim 1 wherein theagents are administered in a dosage form selected from the groupconsisting of a tablet, a multiparticulate formulation for oraladministration; a solution, a sustained release formulation, asuspension or elixir for oral administration, an injectable formulation,an implantable device, a topical preparation, a transdermal deliverydevice, a suppository, a buccal tablet, and an inhalation formulation.8. The method of claim 7, wherein the dosage form is further defined asa solid oral dosage form formulated as a tablet or capsule.
 9. Themethod of claim 1, wherein the ratio of dextromethorphan to tramadol isfrom about 15:1 to 1:15.
 10. The method of claim 9, wherein the ratio ofdextromethorphan to tramadol is from about 10:1 to 1:10.
 11. The methodof claim 10, wherein the ratio of dextromethorphan to tramadol is fromabout 5:1 to 1:5.
 12. The method of claim 11, wherein the ratio ofdextromethorphan to tramadol is about 1:2.
 13. The method of claim 1,wherein caffeine is included as an agent.
 14. A pharmaceuticalcomposition comprising a therapeutically effective amount of acombination of agents, the combination comprising a) dextromethorphan ora pharmaceutically acceptable salt thereof, b) tramadol or apharmaceutically acceptable salt thereof, and c) sildenafil or apharmaceutically acceptable salt thereof.
 15. The pharmaceuticalcomposition of claim 14, wherein the pharmaceutical composition furthercomprises caffeine.